当前期刊: Neurobiology of Learning and Memory Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Differential effects of corticotropin-releasing factor and acute stress on different forms of risk/reward decision-making
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-17
    Courtney A. Bryce; Alexandra J. Adalbert; Mona M. Claes; Mieke van Holstein; Stan B. Floresco

    Acute stress and corticotropin-releasing factor (CRF) have been show to perturb cost/benefit decision making involving effort costs. However, previous studies on how stress manipulations affect decisions involving reward uncertainty have yielded variable results. To provide additional insight into this issue, the current study investigated how central CRF infusion and acute restraint stress alter different forms of risk/reward decision-making guided by internal representations of risk/reward contingencies or external informative cues. Male rats were well-trained on one of two tasks that required choice between a small/certain or a large/risky reward. On a probabilistic discounting task, the probability of obtaining the larger reward increased or decreased systematically over blocks of trials (100-6.25%). On a cue-guided Blackjack task, reward probabilities (50% or 12.5%) were signaled by discriminative auditory cues. CRF (1 or 3μg) was infused intracerebroventricularly (ICV) or one-hour of restraint stress was administered prior to behavioral testing. Neither CRF nor acute stress altered risky choice on probabilistic discounting, but did increase trial omissions in the latter part of the session. Conversely on the Blackjack task, CRF reduced risky choice on good-odds trials (50%), whereas acute stress increased reward sensitivity. CRF but not acute stress also slowed decision latencies across tasks. These data reveal complex and differential manners in which increased CRF activity and acute stress alter distinct forms of risk/reward decision-making, particularly those guided by external cues.

    更新日期:2020-01-17
  • Sleep deprivation directly following eyeblink-conditioning impairs memory consolidation
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-14
    Chris I. De Zeeuw; Cathrin B. Canto

    The relation between sleep and different forms of memory formation continues to be a relevant topic in our daily life. Sleep has been found to affect cerebellum-dependent procedural memory formation, but it remains to be elucidated to what extent the level of sleep deprivation directly after motor training also influences our ability to store and retrieve memories. Here, we studied the effect of disturbed sleep in mice during two different time-windows, one covering the first four hours following eyeblink conditioning (EBC) and another window following the next period of four hours. Compared to control mice with sleep ad libitum, the percentage of conditioned responses and their amplitude were impaired when mice were deprived of sleep directly after conditioning. This impairment was still significant when the learned EBC responses were extinguished and later reacquired. However, consolidation of eyeblink responses was not affected when mice were deprived later than four hours after acquisition, not even when tested during a different day-night cycle for control. Moreover, mice that slept longer directly following EBC showed a tendency for more conditioned responses. Our data indicate that consolidation of motor memories can benefit from sleep directly following memory formation.

    更新日期:2020-01-15
  • The search for the engram: Should we look for plastic synapses or information-storing molecules?
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-13
    Jesse James Langille; Charles Randy Gallistel

    Karl Lashley began the search for the engram nearly seventy years ago. In the time since, much has been learned but divisions remain. In the contemporary neurobiology of learning and memory, two profoundly different conceptions contend: the associative/connectionist (A/C) conception and the computational/representational (C/R) conception. Both theories ground themselves in the belief that the mind is emergent from the properties and processes of a material brain. Where these theories differ is in their description of what the neurobiological substrate of memory is and where it resides in the brain. The A/C theory of memory emphasizes the need to distinguish memory cognition from the memory engram and postulates that memory cognition is an emergent property of patterned neural activity routed through engram circuits. In this model, learning re-organizes synapse association strengths to guide future neural activity. Importantly, the version of the A/C theory advocated for here contends that synaptic change is not symbolic and, despite normally being necessary, is not sufficient for memory cognition. Instead, synaptic change provides the capacity and a blueprint for reinstating symbolic patterns of neural activity. Unlike the A/C theory, which posits that memory emerges at the circuit level, the C/R conception suggests that memory manifests at the level of intracellular molecular structures. In C/R theory, these intracellular structures are information-conveying and have properties compatible with the view that brain computation utilizes a read/write memory, functionally similar to that in a computer. New research has energized both sides and highlighted the need for new discussion. Both theories, the key questions each theory has yet to resolve and several potential paths forward are presented here.

    更新日期:2020-01-13
  • Motor learning and COMT Val158met polymorphism: analyses of oculomotor behavior and corticocortical communication
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-09
    Nathálya Gardênia de Holanda Marinho Nogueira; Débora Marques de Miranda; Maicon Rodrigues Albuquerque; Bárbara de Paula Ferreira; Marco Túlio Silva Batista; Juliana Otoni Parma; Tércio Apolinário-Souza; Lucas Eduardo Antunes Bicalho; Herbert Ugrinowitsch; Guilherme Menezes Lage

    Differences in motor learning can be partially explained by differences in genotype. The catechol-O-methyltransferase (COMT) Val158Met polymorphism regulates the dopamine (DA) availability in the prefrontal cortex modulating motor learning and performance. Given the differences in tonic and phasic DA transmission, this study aimed to investigate whether the greater cognitive flexibility associated with the Val allele would favor the learning of movement parametrization, while the greater cognitive stability associated with the Met allele favors the acquisition of the movement pattern. Furthermore, we investigated if the genotypic characteristics impact visual scanning of information related to parametrization and to the movement pattern, and the level of cortical connectivity associated with motor planning and control. Performance and learning of a sequential motor task were compared among three genotypes (Val/Val, Val/Met, and Met/Met), as well as their oculomotor behavior and level of cortical coherence. The findings show that the cognitive flexibility promoted by the Val allele is associated with a better parametrization. The search for information through visual scanning was specific to each genotype. Also, a greater cortical connectivity associated with the Val allele was found. The combined study of behavioral, electrophysiological and molecular levels of analysis showed that the cognitive stability and flexibility associated with the COMT alleles, influence specific aspects of motor learning.

    更新日期:2020-01-09
  • Some Factors that Restore Goal-Direction to a Habitual Behavior
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-09
    Sydney Trask; Megan L. Shipman; John T. Green; Mark E. Bouton

    Recent findings from our laboratory suggest that an extensively-practiced instrumental behavior can appear to be a goal-directed action (rather than a habit) when a second behavior is added and reinforced during intermixed final sessions (Shipman, Trask, Bouton, & Green, 2018). The present experiments were designed to explore and understand this finding. All used the taste aversion method of devaluing the reinforcer to distinguish between goal-directed actions and habits. Experiment 1 confirmed that reinforcing a second response in a separate context (but not mere exposure to that context) can return an extensively-trained habit to the status of goal-directed action. Experiment 2 showed that training of the second response needs to be intermixed with training of the first response to produce this effect; training the second response after the first-response training was complete preserved the first response as a habit. Experiment 3 demonstrated that reinforcing the second response with a different reinforcer breaks the habit status of the first response. Experiment 4 found that free reinforcers (that were not response-contingent) were sufficient to restore goal-directed performance. Together, the results suggest that unexpected reinforcer delivery can render a habitual response goal-directed again.

    更新日期:2020-01-09
  • Instrumental learning in a mouse model for obsessive-compulsive disorder: Impaired habit formation in Sapap3 mutants
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-09
    I. Ehmer; M. Feenstra; I. Willuhn; D. Denys

    It has been hypothesized that maladaptive habit formation contributes to compulsivity in psychiatric disorders such as obsessive-compulsive disorder (OCD). Here, we used an established animal model of OCD, Sapap3 knockout mice (SAPAP3-/-), to investigate the balance of goal-directed and habitual behavior in compulsive individuals and if altered habit formation is associated with compulsive-like behavior. We subjected 24 SAPAP3-/- and 24 wildtype littermates (WT) to two different schedules of reinforcement in a within-subjects design: a random-ratio (RR) schedule to promote goal-directedness, and a random-interval (RI) schedule, known to facilitate habitual responding. SAPAP3-/- acquired responding under both schedules, but showed lower response rates and fewer attempts to collect food pellets than WT, indicative of altered reward processing. As expected, WT were sensitive to sensory-specific satiety (outcome devaluation) following RR training, but not RI training, demonstrating schedule-specific acquisition of goal-directed and habitual responding, respectively. In contrast, SAPAP3-/- were sensitive to outcome devaluation after both RR and RI training, suggesting decreased engagement of a habitual response strategy. No linear relation was observed between increased grooming and behavior during the outcome devaluation test in SAPAP3-/-. Together, our findings demonstrate altered reward processing and impaired habit learning in SAPAP3-/-. We report a diminished propensity to form habits in these mice, which albeit inconsistent with the predominant idea of excessive habit formation in OCD, nonetheless points at dysregulation of behavioral automation in the context of compulsivity. Thus, the habit hypothesis of compulsivity should be updated to state that an imbalance of habitual and goal-directed responding in either direction can contribute to the development of compulsive behavior.

    更新日期:2020-01-09
  • Unexpected food outcomes can return a habit to goal-directed action
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-09
    Mark E. Bouton; Matthew C. Broomer; Catalina N. Rey; Eric A. Thrailkill

    Three experiments examined the return of a habitual instrumental response to the status of goal-directed action. In all experiments, rats received extensive training in which lever pressing was reinforced with food pellets on a random-interval schedule of reinforcement. In Experiment 1, the extensively-trained response was not affected by conditioning a taste aversion to the reinforcer, and was therefore considered a habit. However, if the response had earned a new and unexpected food pellet during the final training session, the response was affected by taste aversion conditioning to the (first) reinforcer, and had thus been converted to a goal-directed action. In Experiment 3, 30 mins of prefeeding with an irrelevant food pellet immediately before the test also converted a habit back to action, as judged by the taste-aversion devaluation method. That result was consistent with difficulty in finding evidence of habit with the sensory-specific satiety method after extensive instrumental training (Experiment 2). The results suggest that an instrumental behavior’s status as a habit is not permanent, and that a habit can be returned to action status by associating it with a surprising reinforcer (Experiment 1) or by giving the animal an unexpected prefeeding immediately prior to the action/habit test (Experiment 3).

    更新日期:2020-01-09
  • Threat-induced modulation of hippocampal and striatal memory systems during navigation of a virtual environment
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-07
    Jarid Goodman; Mason McClay; Joseph E. Dunsmoor

    The brain is composed of multiple memory systems that mediate distinct types of navigation. The hippocampus is important for encoding and retrieving allocentric spatial cognitive maps, while the dorsal striatum mediates procedural memories based on stimulus-response (S-R) associations. These memory systems are differentially affected by emotional arousal. In particular, rodent studies show that stress typically impairs hippocampal spatial memory while it spares or sometimes enhances striatal S-R memory. The influence of emotional arousal on these separate navigational memory systems has received less attention in human subjects. We investigated the effect of dynamic changes in anticipatory anxiety on hippocampal spatial and dorsal striatal S-R memory systems while participants attempted to solve a virtual eight-arm radial maze. In Experiment 1, participants completed a hippocampus-dependent spatial version of the eight-arm radial maze that required allocentric spatial memory to successfully navigate the environment. In Experiment 2, participants completed a dorsal striatal S-R version of the maze where no allocentric spatial cues were present, requiring the use of S-R navigation. Anticipatory anxiety was modulated via threat of receiving an unpleasant electrical shock to the wrist during memory retrieval. Results showed that threat of shock was associated with more errors and increased use of non-spatial navigational strategies in the hippocampal spatial task, but did not influence memory performance in the striatal S-R task. Findings indicate a dissociation regarding the influence of anticipatory anxiety on memory systems that has implications for understanding how fear and anxiety contribute to memory-related symptoms in human psychopathologies.

    更新日期:2020-01-07
  • Blocking under stress: Sustained attention to stimuli without predictive value?
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-03
    Franziska Magdalena Kausche; Lars Schwabe

    Learning is blocked when a stimulus is followed by an outcome that is identical to what was expected and thus contains no new information. This classic ‘blocking’ effect exemplifies that learning is driven by the predictive value of stimuli, which in turn should guide the allocation of attentional resources. Stress is known to be a powerful modulator of learning and memory. However, whether stress may affect attentional processing during predictive learning is largely unknown. Here, we combined electroencephalography and eye-tracking with an experimental stress manipulation and a fear conditioning paradigm designed to probe the blocking effect, to determine if and how stress impacts efficient attentional processing during predictive learning. Participants’ explicit ratings indicated, irrespective of stress, a blocking effect. The control group further showed preferential attentional processing of predictive vs. unpredictive stimuli, reflected in differential fixation durations and a differential N2pc. Stress abolished this differentiation and led even to sustained attention, indicated by higher late positive potentials, to stimuli with low predictive value. Moreover, stress resulted in an overall increase in the P3b during the blocking phase, suggesting increased attentional processing, presumably due to impaired access to previously learned associations. Together, our results suggest that while control participants paid particular attention to predictive stimuli and reduced attention to unpredictive stimuli, in line with the classic blocking effect, stress before learning reduced this preferential processing. Thus, the present findings highlight the role of attention allocation for predictive fear learning and suggest that stress may impair efficient information processing against the background of prior experiences.

    更新日期:2020-01-04
  • The D2-family receptor agonist bromocriptine but, not nicotine, reverses NMDA receptor antagonist-induced working memory deficits in the radial arm maze in mice
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-03
    David A. MacQueen; Jared W. Young

    Hypofunction of the NMDA receptor (NMDAr) may underlie cognitive deficits associated with schizophrenia and other psychiatric conditions including working memory (WM) impairments. Given that these deficits link closely to functional outcome, treatments remediating such deficits require identification. NMDAr hypofunction can be modeled via treatment with the antagonist MK-801. Hence, the present study determined whether cholinergic or dopaminergic agonists attenuate MK-801-induced WM deficits in mice. WM was assessed in male C57BL/6 mice trained on an automated 12-arm radial arm maze (RAM) paradigm, wherein rewards were delivered after the first but, not after subsequent entries into WM arms (8/12) and never delivered for entries into reference memory (RM) arms (4/12). Mice were then treated with MK-801 (vehicle or 0.3 mg/kg) and nicotine (vehicle, 0.03 or 0.30 mg/kg) in a cross-over design. After a 2-week washout, mice were then retested with MK-801 and the dopamine D2-family receptor agonist bromocriptine (vehicle, 3 or 10 mg/kg). In both experiments, MK-801 reduced WM span and increased RM and WM error rates. Nicotine did not attenuate these deficits. In contrast, a bromocriptine/MK-801 interaction was observed on WM error rate, where bromocriptine attenuated MK-801 induced deficits without affecting MK-801-induced RM errors. Additionally, bromocriptine produced the main effect of slowing latency to collect rewards. Hence, while NMDAr hypofunction-induced deficits in WM was unaffected by nicotine, it was remediated by treatment with the dopamine D2-family agonist bromocriptine. Future studies should determine whether selective activation of dopamine D2, D3, or D4 receptors remediate this NMDAr hypofunction-induced WM deficit.

    更新日期:2020-01-04
  • Temporal dynamics of Arc/Arg3.1 expression in the dorsal striatum during acquisition and consolidation of a motor skill in mice
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-02
    Wan-Kun Gong; Jian Ni; Lan-Fang Yu; Lu Wang; Zhi-Li Huang

    Region- and pathway-specific plasticity within striatal circuits is critically involved in the acquisition and long-term retention of a new motor skill as it becomes automatized. However, the molecular substrates contributing to this plasticity remain unclear. Here, we examined the expression of the activity-regulated cytoskeleton-associated protein (Arc) in the associative or dorsomedial striatum (DMS) and the sensorimotor or dorsolateral striatum (DLS), as well as in striatonigral and striatopallidal neurons, during different skill learning phases in the accelerating rotarod task. We found that Arc was mainly expressed in the DMS during early motor learning and progressively increased in the DLS during gradual motor skill consolidation. Moreover, Arc was preferentially expressed in striatopallidal neurons early in training and gradually increased in striatonigral neurons later in training. These data demonstrate that in the dorsal striatum, the expression of Arc exhibits a region- and cell-specific transfer during the learning of a motor skill, suggesting a link between striatal Arc expression and motor skill learning in mice.

    更新日期:2020-01-02
  • Chronic ghrelin administration suppresses IKK/NF-κB/BACE1 mediated Aβ production in primary neurons and improves cognitive function via upregulation of PP1 in STZ-diabetic rats
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-02
    Lou-Yan Ma; Song-Fang Liu; Jun-Hui Du; Yu Niu; Peng-Fei Hou; Qing Shu; Ran-Ran Ma; Song-Di Wu; Qiu-Min Qu; Ya-Li Lv

    Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aβ expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aβ production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aβ in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aβ production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aβ production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aβ production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aβ production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.

    更新日期:2020-01-02
  • Modulation of the MAPKs pathways affects Aβ-induced cognitive deficits in Alzheimer’s disease via activation of α7nAChR
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2020-01-02
    Ke-Wei Chang; Hang-Fan Zong; Mohammad Yasir Rizvi; Kai-Ge Ma; Wanying Zhai; Meng Wang; Wei-Na Yang; Sheng-Feng Ji; Yi-Hua Qian

    Cognitive impairment in Alzheimer’s disease (AD) is characterized by being deficient at learning and memory. Aβ1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aβ-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aβ internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aβ-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aβ-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aβ-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.

    更新日期:2020-01-02
  • Stimulus modality influences the acquisition and use of the rule-based strategy and the similarity-based strategy in category learning
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-24
    Jie Wu; Qiufang Fu; Michael Rose

    This study aimed to investigate whether stimulus modality influenced the acquisition and use of the rule-based strategy and the similarity-based strategy in category learning and whether the use of the two strategies was supported by shared or separate neural substrates. To address these issues, we combined behavioral and fNIRS methods in a modified prototype distortion task in which each category member has one rule feature and ten similarity features, and each type of feature can be presented in either the visual modality or the auditory modality. The results in Experiment 1 revealed that the learning effect in the “auditory rule-visual similarity” condition was the highest among all four conditions; further analysis revealed that in the “auditory rule-visual similarity” condition, the number of participants who used the rule-based strategy was more than the number of participants who used the similarity-based strategy, and the learning effect was always much higher for the rule-based strategy than for the similarity-based strategy. The behavioral results in Experiment 2 replicated the main findings in Experiment 1, and the fNIRS results showed that the use of the visual rule-based strategy was mediated by the dorsolateral prefrontal cortex, whereas the use of the auditory similarity-based strategy mainly engaged in the superior temporal gyrus, and the use of the visual similarity-based strategy mainly engaged in the inferior temporal gyrus. The results in Experiment 3 revealed that when the stimuli had only one type of feature, the visual rule rather than the auditory rule was learned more easily. The results provide new evidence that the stimulus modality can influence the acquisition and use of the rule-based strategy and the similarity-based strategy in category learning and that the use of the two types of strategies is supported by separate neural substrates both in the auditory modality and the visual modality.

    更新日期:2019-12-25
  • Involvement of medial prefrontal cortex NMDA and AMPA/kainate glutamate receptors in social recognition memory consolidation
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-24
    Lucas Aschidamini Marcondes; Eduarda Godfried Nachtigall; André Zanluchi; Jociane de Carvalho Myskiw; Ivan Izquierdo; Cristiane Regina Guerino Furini

    Social recognition memory (SRM) enables the distinction between familiar and strange conspecifics, a fundamental ability for sociable species, such as rodents and humans. There is mounting evidence that the medial prefrontal cortex plays a prominent role both in shaping social behavior and in recognition memory. Glutamate is the major excitatory neurotransmitter in the brain, and activity of its ionotropic receptors is known to mediate both synaptic plasticity and consolidation of various types of memories. However, whether these receptors are required in the medial prefrontal cortex (mPFC) for SRM consolidation remains elusive. To address this issue, we submitted rats to a social discrimination paradigm, administered infusions of NMDA- and AMPA/kainate-receptors antagonists into the prelimbic (PrL) subdivision of the mPFC at different post-encoding time points and evaluated long-term memory retention twenty-four hours later. We found that blocking NMDA receptors immediately after the sample phase, but not 3 h later, impaired SRM consolidation, whereas the blockade of AMPA/kainate receptors immediately and 3 h, but not 6 h after the sample phase, prevented long-term memory consolidation. These results highlight the importance of the mPFC in social cognition and may contribute towards the understanding of the dysfunctional social information processing that underlies multiple neuropsychiatric disorders.

    更新日期:2019-12-25
  • Multiple extinction contexts modulate the neural correlates of context-dependent extinction learning and retrieval
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-24
    Andrea Hermann; Rudolf Stark; Eva A. Müller; Onno Kruse; Oliver T. Wolf; Christian J. Merz

    Exposure therapy is a successful treatment for patients with anxiety and fear-related disorders. Extinction of conditioned fear comprises one important mechanism underlying the effects of exposure therapy. Yet, relapses frequently occur in the long-term, probably related to difficulties in generalizing the extinction of conditioned fear to new contexts, leading to renewal of conditioned fear. Extinction training in multiple extinction contexts depicts a promising opportunity to reduce this renewal of conditioned fear. However, the underlying neural correlates are unknown yet. In this functional magnetic resonance imaging study, 49 healthy men participated in a fear conditioning paradigm with fear acquisition training in context A on a first day, extinction training in a single context (B1) or in four different contexts (B1-B4) one day later, and fear and extinction recall and reinstatement in context B1 and a novel context C on a third day one week later. Multiple extinction contexts led to a stronger differential activation decrease in the hippocampus during extinction learning compared to a single extinction context. One week later, the multiple context group compared with the single context group showed reduced differential amygdala activation during fear renewal in the novel context C compared with the extinction context B1. Furthermore, multiple extinction contexts diminished amygdala activation during a subsequent reinstatement test in context B1. However, there were no significant differences in differential conditioned SCRs. These results indicate that the use of multiple extinction contexts during extinction training leads to reduced conditioned responses in the amygdala-hippocampus complex.

    更新日期:2019-12-25
  • Differential effects of L- and D- lactate on memory encoding and consolidation: Potential role of HCAR1 signaling
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-24
    Claire J. Scavuzzo; Irina Rakotovao; Clayton T. Dickson

    The process of memory consolidation is energy-demanding and brain energy deficits result in memory impairments. Indeed, L-lactate, a preferred neuronal energy substrate, enhances the formation of memory, while blockade of the neuronal uptake of L-lactate by either pharmacological means or using its enantiomer D-lactate, impairs memory. Beyond metabolism, both enantiomers of lactate also have signaling properties through the hydroxycarboxylic acid receptor 1 (HCAR1). Thus far, paradigms testing for an effect of lactate on memory modulation have ignored HCAR1 signaling while also mainly performing manipulations before learning and using intracranial administration techniques. Using an inhibitory avoidance (IA) memory protocol, the present study examined the effects on of systemic administration of both L- and D-lactate as well as the specific HCAR1 agonist 3,5-dihydroxybenzoic acid (3,5-DHBA) across the pre- and post-training periods. We found that post-training subcutaneous injections of either 3,5-DHBA or D-lactate significantly enhanced memory compared to saline controls, whereas L-lactate had no effect, suggesting that HCAR1 signaling in the absence of lactate metabolism supports memory consolidation processes. When administered 15 minutes prior to training, D-lactate and 3,5-DHBA impaired memory compared to saline controls. In contrast, L-lactate treated rats showed memory enhancements as compared to D-lactate-treated rats. Taken together, these results suggest different roles for lactate at different memory stages. It is likely that a metabolic role is at play during learning while HCAR1 signaling may play a greater role during consolidation.

    更新日期:2019-12-25
  • More dynamic, more quantitative, unexpectedly intricate: advanced understanding on synaptic RNA localization in learning and memory
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-24
    Rohini Roy; Nobuyuki Shiina; Dan Ohtan Wang

    Synaptic signaling exhibits great diversity, complexity, and plasticity which necessitates maintenance and rapid modification of a local proteome. One solution neurons actively exploit to meet such demands is the strategic deposition of mRNAs encoding both proteins for basal activities and experience-driven activities into ribonucleoprotein complexes at the synapse. Transcripts localized in this manner can be rapidly accessed for translation in response to a diverse range of stimuli in a temporal- and spatially-restricted manner. Here we review recent findings on localized RNAs and RNA binding proteins in the context of learning and memory, as revealed by cutting-edge in-vitro and in-vivo technologies capable of yielding quantitative and dynamic information. The new technologies include proteomic and transcriptomic analyses, high-resolution multiplexed RNA imaging, single-molecule RNA tracking in living neurons, animal models and human neuron cell models. Among many recent advances in the field, RNA chemical modification has emerged as one of the new regulatory layers of gene expression at synapse that is complex and yet largely unexplored. These exciting new discoveries have enhanced our understanding of the modulation mechanisms of synaptic gene expression and their roles in cognition.

    更新日期:2019-12-25
  • Effects of Circadian Rhythm Disorder on the Hippocampus of SHR and WKY Rats
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-16
    YunLei Wang; YuGe Zhang; WenZhu Wang; Xu Liu; YaFei Chi; JianFeng Lei; BaoGui Zhang; Tong Zhang

    The present study investigated the effects of circadian rhythm disorder (CRD) on the hippocampus of SHR and WKY rats. Male SHR rats (n = 27) and WKY rats (n = 27) were randomly divided into six groups: SHR and WKY normal (N)CR, SHR and WKY CRD 16/8 (CRD16/8), and SHR and WKY CRD 12/12 (CRD12/12). Activity patterns were adjusted using different photoperiods over 90 days and any changes were recorded. Rats were tested in the Morris water maze and in a novel object recognition experiment; serologic analysis, magnetic resonance imaging (diffusion tensor imaging + arterial spin labeling), hippocampal Nissl staining, Fluoro-Jade B staining, and immunohistochemistry were also performed. The results showed that both types of inverted photoperiod reduced CR amplitude and prolonged the circadian period. CRD and hypertension reduced memory performance and novel object recognition and preference. The decreases in memory and preference indices were greater in rats in the CRD12/12 group compared to the CRD16/8 group. CRD and hypertension decreased fractional anisotropy values, the number of neurons and astrocytes in the hippocampus, and the expression of brain-derived neurotrophic factor and synapsin 1; it also enhanced the degeneration of neurons and microglia and reduced blood flow in the hippocampus, and increased nuclear factor κB, caspase, neuron-specific enolase, and interleukin-6 levels. These findings reveal a biological basis for the link between CRD and cognitive decline, which has implications for CRD caused by shift work and other factors.

    更新日期:2019-12-17
  • Evidence that a defined population of neurons in lateral amygdala is directly involved in auditory fear learning and memory
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-13
    Christopher W. Butler; Yvette M. Wilson; Samuel A. Mills; Jenny M. Gunnersen; Mark Murphy

    Memory is thought to be encoded within networks of neurons within the brain, but the identity of the neurons involved and circuits they form have not been described for any memory. Previously, we used fos-tau-lacZ (FTL) transgenic mice to identify discrete populations of neurons in different regions of the brain which were specifically activated following fear conditioning. This suggested that these populations of neurons form nodes in a network that encodes fear memory. In particular, one population of learning activated neurons was found within a discrete region of the lateral amygdala (LA), a key nucleus required for fear conditioning. In order to provide evidence that this population is directly involved in fear conditioning, we have analysed the expression of a key molecular requirement for fear conditioning in LA, phosphorylated Extracellular Signal Regulated Kinase 1 and 2 (pERK1/2). The only neurons in LA that specifically expressed pERK1/2 following auditory fear conditioning were in the ventrolateral nucleus of the LA (LAvl), in the same discrete region where we found learning specific FTL+ neurons. Double labelling experiments in FTL mice showed that a substantial proportion of the learning activated neurons expressed both pERK1/2 and FTL. These experiments provide clear evidence that the learning specific neurons we identified within LAvl are directly involved in auditory fear conditioning. In addition, learning specific expression of pERK1/2 was found in a dense network of dendrites contained within the border region of the LAvl. This network of dendrites may represent an activated dendritic field involved in fear conditioning in LA.

    更新日期:2019-12-13
  • Effects of parietal exogenous oscillatory field potentials on subjectively perceived memory confidence
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-13
    Syanah C. Wynn; Roy P.C. Kessels; Dennis J.L.G. Schutter

    Previous research has suggested involvement of parietal theta (3-7 Hz) power in subjectively perceived memory confidence during retrieval. To obtain further insights into the role of parietal theta activity during retrieval in processes associated with performance and confidence, fifty-four healthy volunteers performed a recognition memory task in a within-subject transcranial alternating current stimulation (tACS) study. Participants encoded a subset of words at specific on-screen locations. During the retrieval phase accuracy and subjectively perceived confidence on item and source memory were evaluated while administering exogenous alternating field potentials. Results showed that 3.5 Hz tACS decreased subjectively perceived memory confidence as compared to sham and 8 Hz tACS. No tACS effects were found on accuracy regarding item and source memory. Our findings suggest that theta activity in the parietal cortex is involved in subjective perceived confidence in word recognition.

    更新日期:2019-12-13
  • Naloxone-precipitated withdrawal ameliorates impairment of cost-benefit decision making in morphine-treated rats: involvement of BDNF, p-GSK3-β, and p-CREB in the amygdala
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-13
    Zahra Fatahi; Arman Zeinaddini-Meymand; Saeideh Karimi-Haghighi; Marzieh Moradi; Fariba Khodagholi; Abbas Haghparast

    Several studies indicated that morphine administration impairs cognitive brain functions. Therefore, in the current study, we investigated the effect of subchronic exposure to morphine and its withdrawal on effort- and/or delay-based forms of cost-benefit decision making and alterations in p-CREB/CREB ratio, p-GSK3β/GSK3β ratio, and BDNF level during decision making in the amygdala. Our data displayed an impairment of both forms of cost-benefit decision making following subchronic exposure to morphine. However, preference of high reward/high effort and/or high delay reward increased after naloxone injection. In molecular section, levels of BDNF and p-CREB/CREB ratio increased during cost-benefit decision making while p-GSK3β/GSK3β ratio decreased in both forms of decision making. In morphine-treated rats, level of BDNF and p-CREB/CREB ratio reduced during both forms of decision making while p-GSK3β/ GSK3β ratio increased during delay-based and did not have a significant difference with the control group during effort-based decision making. On the withdrawal day, BDNF level raised while p-GSK3β/GSK3β ratio attenuated compared to morphine-treated group in both form of decision making. In addition, p-CREB/CREB ratio increased only during delay-based decision making on the withdrawal day. In conclusion, our data revealed that subchronic exposure to morphine interferes with the cost-benefit decision making may be via changes in level of BDNF, p-CREB/CREB and p-GSK3β/ GSK3β ratio in the amygdala.

    更新日期:2019-12-13
  • Prefrontal but not cerebellar tDCS attenuates renewal of extinguished conditioned eyeblink responses
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-12
    J. Lipp; R. Draganova; G. Batsikadze; TM. Ernst; M. Uengoer; D. Timmann

    An extended neural network is known to underlie extinction learning. As yet, comparatively little is known about the possible contribution of the cerebellum and the dorsolateral prefrontal cortex (dlPFC). In the present study, transcranial direct current stimulation (tDCS) was used to provide further evidence that the dlPFC and the cerebellum are involved in extinction-related processes. A total of 100 young and healthy human participants were randomly assigned to one of five stimulation groups: 1) anodal tDCS of the cerebellum, 2) cathodal tDCS of the cerebellum, 3) anodal tDCS of the dlPFC, 4) cathodal tDCS of the dlPFC, and 5) sham stimulation. Participants underwent delay eyeblink conditioning using an A-B-A/B renewal paradigm. Two different colors of background light (orange and blue) were used as contexts. On day 1, acquisition of conditioned eyeblink responses was performed in context A, followed by extinction in context B. tDCS was applied during extinction. On day 2, extinction recall was tested in contexts A and B with higher incidence of conditioned responses in acquisition context A compared to extinction context B indicating renewal effects. All groups showed significant effects of acquisition of conditioned eyeblink responses and significant effects of extinction. There was no significant difference in extinction between stimulation groups. During extinction recall, renewal effects were present in all groups, except the group which had received anodal tDCS of the dlPFC during extinction. In the present study, no direct effects of dlPFC or cerebellar tDCS were demonstrated on extinction. Anodal tDCS of the dlPFC, but not the cerebellum, resulted in delayed effects on context-related processes of extinction, possibly explained by shifting attention away from the context and towards the conditioned stimulus during extinction learning. Anodal tDCS of the dlPFC attenuated context-related recall of learned aversive responses. Effects of tDCS, however, were weak and need to be confirmed in future studies. Lack of cerebellar tDCS effects do not exclude a possible role of the cerebellum in extinction-related processes, and are likely explained by methodological limitations of cerebellar tDCS.

    更新日期:2019-12-13
  • Modulation of Intrinsic Excitability as a Function of Learning within the Fear Conditioning Circuit
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-09
    Hanna Yousuf, Vanessa L. Ehlers, Megha Sehgal, Chenghui Song, James R. Moyer

    Experience-dependent neuronal plasticity is a fundamental substrate of learning and memory. Intrinsic excitability is a form of neuronal plasticity that can be altered by learning and indicates the pattern of neuronal responding to external stimuli (e.g. a learning or synaptic event). Associative fear conditioning is one form of learning that alters intrinsic excitability, reflecting an experience-dependent change in neuronal function. After fear conditioning, intrinsic excitability changes are evident in brain regions that are a critical part of the fear circuit, including the amygdala, hippocampus, retrosplenial cortex, and prefrontal cortex. Some of these changes are transient and/or reversed by extinction as well as learning-specific (i.e. they are not observed in neurons from control animals). This review will explore how intrinsic neuronal excitability changes within brain structures that are critical for fear learning, and it will also discuss evidence promoting intrinsic excitability as a vital mechanism of associative fear memories. This work has raised interesting questions regarding the role of fear learning in changes of intrinsic excitability within specific subpopulations of neurons, including those that express immediate early genes and thus demonstrate experience-dependent activity, as well as in neurons classified as having a specific firing type (e.g. burst-spiking vs. regular-spiking). These findings have interesting implications for how intrinsic excitability can serve as a neural substrate of learning and memory, and suggest that intrinsic plasticity within specific subpopulations of neurons may promote consolidation of the memory trace in a flexible and efficient manner.

    更新日期:2019-12-09
  • Hippocampal HECT E3 Ligase inhibition facilitates consolidation, retrieval, and reconsolidation, and inhibits extinction of contextual fear memory
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-09
    Jadier Redondo Cotes, Bruno Popik, Mirelle Casagrande, Mateus Oliveira Silva, Jorge Alberto Quillfeldt, Lucas de Oliveira Alvares, Tadeu Mello e Souza

    Ubiquitination is involved in synaptic plasticity and memory, but the involvement of HECT E3 ligases in these processes has not yet been established. Here, we bilaterally infused heclin, a specific inhibitor of these ligases, into the dorsal hippocampus of male Wistar rats that were trained in a contextual fear conditioning. Heclin improved short-term memory, consolidation, retrieval, and reconsolidation when administered immediately post training, prior to testing, or after memory reactivation, respectively. In addition, it impaired memory extinction when administered prior to a long reactivation session. Heclin infusion was also tested for locomotor activity and anxiety-like behavior in a circular arena, but no effect was seen. Taken together, these results indicate that HECT E3 ligases are involved in the modulation of fear memory.

    更新日期:2019-12-09
  • Sub-anesthetic and anesthetic ketamine produce different long-lasting behavioral phenotypes (24 h post-treatment) via inducing different brain-derived neurotrophic factor (BDNF) expression level in the hippocampus
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-12-05
    Chunhui Wu, Yu Wang, Yang He, Song Wu, Zhifei Xie, Jian Zhang, Jingshan Shen, Zhen Wang, Ling He

    Clinical and preclinical researches have shown that sub-anesthetic ketamine elicits sustained antidepressant effects for up to 1-2 weeks. Pharmacokinetics studies (t1/2 = 23 min) in mice showed no ketamine residue at 24 h after sub-anesthetic or anesthetic ketamine administration. Therefore, this study aims to reveal the mechanism underlying these different biological functions at 24 h after sub-anesthetic and anesthetic ketamine treatment. First, at the animal behavioral level, we found that sub-anesthetic ketamine induced antidepressant and anxiolytic effects while anesthetic ketamine induced depressive-like phenotypes and cognitive impairment. Second, we examined the correlation between behavior phenotype and protein expression, and found that the Brain-derived neurotrophic factor (BDNF) level is oppositely regulated by sub-anesthetic and anesthetic ketamine. Sub-anesthetic ketamine significantly increased the BDNF level, correlating to antidepressant effects; whereas anesthetic dose reduced BDNF expression in the hippocampus, correlating to depressive-like behaviors, anxiety-like behaviors and cognitive impairment. Third, the antidepressant effects of sub-anesthetic ketamine were prevented by pre-treatment of ANA-12, a Tropomyosin receptor kinase B (TrkB) inhibitor. Thus, we conclude that BDNF may be the key factor underlying antidepressant and anxiolytic effects of sub-anesthetic ketamine at 24 h after treatment. These results may shed light on future studies and the development of long-lasting anti-depressant drugs and therapies.

    更新日期:2019-12-05
  • Fornix lesions impair place-, but not response-learning in the open-field tower maze
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-29
    Olga Lipatova, Matthew M. Campolattaro, Joseph A. Picone

    The purpose of the present study was to examine hippocampal function for spatial learning in a land-based circular maze (i.e., the open-field tower maze [OFTM]). The OFTM, a task designed to be non-stressful, has been previously used to demonstrate the influence of gonadal hormones on spatial learning. Thus, determination of brain function for navigating in the OFTM provides an important extension to previous knowledge. Fornix lesions were used in the present experiment to disrupt hippocampal processing. After initial pre-training, rats received either an electrolytic fornix lesion surgery or a sham surgery. The rats from each surgical group were given either place- or response-training in the OFTM. The results showed that (1) lesioned place-learners required more trials than sham place-learners to solve the OFTM and (2) lesioned response-learners solved the OFTM at the same rate as sham response-learners. Our findings support the hypothesis that the hippocampus is necessary for place-, but not response-learning in the OFTM task. The OFTM is an appetitive task that does not depend on a choice between restricted directions that a rat would be required to make in a T-maze or a radial arm-maze, and does not include aversive components inherent to a Morris Water Maze or Barnes Maze. Thus, the OFTM can be used to investigate the manipulations of hippocampus-dependent spatial learning without confounding variables related to an animal’s stress level.

    更新日期:2019-11-30
  • Unitization does not impede overall item recognition performance: Behavioral and event-related potential study
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-28
    Zejun Liu, Jun Wu, Yujuan Wang, Chunyan Guo

    It is widely accepted that unitization can promote familiarity-based associative recognition, but the role of unitization in recognition of individual component elements which originate from compound words remains unclear. The goals of this study were to elaborate on how unitization affects item recognition and further examine the effect of unitization on the extent to which familiarity and recollection contribute to item recognition. During the study phase, participants were asked to learn 48 compound words and 48 unrelated word pairs, and during the test phase, they were instructed to distinguish old from new words. We disassociated the contribution of familiarity and recollection to recognition with remember/know paradigm in experiment 1 and with ERPs old/new effects in experiment 2. The results showed that the overall item recognition was equivalent between the two retrieval conditions. Disassociation the contribution of familiarity and recollection, we found that there was higher recollection-based item recognition performance for compound-old words than for unrelated-old words in experiment 1. In contrast, in experiment 2, the magnitude of later parietal old/new effect related to recollection was larger for the former than for the latter, indicating that equivalent levels of memory retrieval were achieved through “less” neural correlates of familiarity and recollection. By synthesizing the results of experiment 1 and 2, we believed unitization did not impede overall item recognition performance.

    更新日期:2019-11-29
  • Learning and Aging Affect Neuronal Excitability and Learning
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-28
    M. Matthew Oh, John F. Disterhoft

    The first study that demonstrated a change in intrinsic neuronal excitability after learning in ex vivo brain tissue slices from a mammal was published over thirty years ago. Numerous other manuscripts describing similar learning-related changes have followed over the years since the original paper demonstrating the postburst afterhyperpolarization (AHP) reduction in CA1 pyramidal neurons from rabbits that learned delay eyeblink conditioning was published. In addition to the learning-related changes, aging-related enlargement of the postburst AHP in CA1 pyramidal neurons have been reported. Extensive work has been done relating slow afterhyperpolarization enhancement in CA1 hippocampus to slowed learning in some aging animals. These reproducible findings strongly implicate modulation of the postburst AHP as an essential cellular mechanism necessary for successful learning, at least in learning tasks that engage CA1 hippocampal pyramidal neurons.

    更新日期:2019-11-29
  • The effects of different protocols of physical exercise and rest on long-term memory
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-26
    Wesley Pyke, Fadi Ifram, Laura Coventry, Yee Sung, Isabelle Champion, Amir-Homayoun Javadi
    更新日期:2019-11-27
  • ERP Evidence for the Effect of Working Memory Span Training on Working Memory Maintenance: A Randomized Controlled Trial
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-26
    Qiumei Zhang, Yang Li, Wan Zhao, Xiongying Chen, Xiaohong Li, Boqi Du, Xiaoxiang Deng, Feng Ji, Chuanyue Wang, Yu-Tao Xiang, Qi Dong, Susanne M. Jaeggi, Chuansheng Chen, Yan Song, Jun Li

    There is a lot of debate in the literature with regards to whether the effects of working memory span training generalize to working memory tasks that are different from the trained task, however, there is little evidence to date supporting this idea. The present randomized controlled trial included 80 undergraduate students who were randomly assigned to either the experimental group (N = 40) or the control group (N = 40) in order to receive a working memory span intervention for 20 sessions over the course of 4 weeks. Brain electrophysiological signals during a dot pattern expectancy (DPX) task and a change detection task were recorded both before and after the intervention. The amplitudes of characteristic event-related potential (ERP) components reflecting working memory maintenance capability during the delay period of both tasks (i.e., the contingent negative variation or CNV, derived from the DPX task, and the contralateral delay activity or CDA, derived from the change detection task) were used as the primary outcome measures. Our data indicated that the intervention resulted in specific changes in both, the CNV and the CDA, suggesting that working memory span training generalized to working memory maintenance processes as observed in working memory tasks that were different from the trained task. We conclude that working memory span training might serve as a useful tool to improve working memory maintenance capability. Trial Registration: Chinese Clinical Trial Registry (chiCTR-INR-17011728).

    更新日期:2019-11-27
  • Shifting between response and place strategies in maze navigation: effects of training, cue availability and functional inactivation of striatum or hippocampus in rats
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-26
    Julien Gasser, Anne Pereira de Vasconcelos, Brigitte Cosquer, Anne-Laurence Boutillier, Jean-Christophe Cassel

    Response and place memory systems have long been considered independent, encoding information in parallel, and involving the striatum and hippocampus, respectively. Most experimental studies supporting this view used simple, repetitive tasks, with unrestrained access to spatial cues. They did not give animals an opportunity to correct a response strategy by shifting to a place one, which would demonstrate dynamic, adaptive interactions between both memory systems in the navigation correction process. In a first experiment, rats were trained in the double-H maze for different durations (1, 6, or 14 days; 4 trials/day) to acquire a repetitive task in darkness (forcing a response memory-based strategy) or normal light (placing response and place memory systems in balance), or to acquire a place memory. All rats were given a misleading shifted-start probe trial 24-hr post-training to test both their strategy and their ability to correct their navigation directly or in response to negative feedback. Additional analyses focused on the dorsal striatum and the dorsal hippocampus using c-Fos gene expression imaging and, in a second experiment, reversible muscimol inactivation. The results indicate that, depending on training protocol and duration, the striatum, which was unexpectedly the first to come into play in the dual strategy task, and the hippocampus are both required when rats have to correct their navigation after having acquired a repetitive task in a cued environment. Partly contradicting the model established by Packard and McGaugh (1996, Neurobiology of Learning and Memory, vol 65), these data point to memory systems that interact in more complex ways than considered so far. To some extent, they also challenge the notion of hippocampus-independent response memory and striatum-independent place memory systems.

    更新日期:2019-11-27
  • BDNF induces in vivo long-lasting enhancement of synaptic transmission and structural reorganization at the hippocampal mossy fibers in a transcription and translation-independent manner
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-23
    Araceli Martínez-Moreno, Alejandro Rivera-Olvera, Martha L. Escobar

    Brain-derived neurotrophic factor (BDNF) is an essential product of protein synthesis with a prominent impact on brain signaling and synaptic plasticity. Exogenous application of this neurotrophin is able to induce long-term potentiation (LTP) in several brain structures such as the hippocampus along with increases in gene transcription and translation of proteins involved in functional and structural plasticity. In this regard, our previous studies have demonstrated that acute intrahippocampal administration of BDNF induces long-lasting enhancement of synaptic transmission at the mossy fibers projection (MF) accompanied by a structural reorganization at the CA3 hippocampus area. Thus, considering the non-canonical molecular mechanisms underlying MF-CA3-LTP and the high expression of this neurotrophin in the CA3 area, we wonder whether transcriptional and translational inhibition interferes with the persistence of the MF functional and structural synaptic plasticity elicited by BDNF in adult rats in vivo. Our results show that BDNF is able to induce a lasting potentiation of synaptic efficacy at the MF projection accompanied by a structural reorganization at the CA3 area in an mRNA synthesis and protein translation-independent manner. The present findings support the idea that BDNF is an essential plasticity related product, which is necessary and sufficient to induce and maintain functional and structural synaptic plasticity at the MF-CA3 pathway.

    更新日期:2019-11-26
  • Learning-induced Intrinsic and Synaptic Plasticity in the Rodent Medial Prefrontal Cortex
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-23
    James T. Porter, Marian T. Sepulveda-Orengo

    In rodents, the anterior cingulate (ACC), prelimbic (PL), and infralimbic cortex (IL) comprise the medial prefrontal cortex (mPFC). Through extensive connections with cortical and subcortical structures, the mPFC plays a key modulatory role in the neuronal circuits underlying associative fear and reward learning. In this article, we have compiled the evidence that associative learning induces plasticity in both the intrinsic and synaptic excitability of mPFC neurons to modulate conditioned fear and cocaine seeking behavior. The literature highlights the accumulating evidence that plasticity in the intrinsic excitability of mPFC neurons represents a major cellular mechanism that interacts with synaptic changes to alter the impact of the mPFC on fear and reward circuits.

    更新日期:2019-11-26
  • Polarity and subfield specific effects of transcranial direct current stimulation on hippocampal plasticity
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-22
    Joyce G. Rohan, Molly K. Miklasevich, Shawn M. McInturf, Naomi A. Bechmann, Raquel J. Moore, Candice Hatcher-Solis, Ryan Jankord

    An increasing number of studies using human subjects substantiate the use of transcranial direct current stimulation (tDCS) as a noninvasive approach to treat various neurological symptoms. tDCS has been tested in conditions from motor to cognition dysfunctions. Performance enhancement of healthy subjects using tDCS has also been explored. The underlying physiological mechanism for tDCS effects is hypothesized to be through changes in neuroplasticity and we have previously demonstrated that in vivo anodal tDCS can enhance neuroplasticity of hippocampal CA1 neurons. The purpose of this study was to determine, whether the underlying electrophysiological changes that occur following in vivo tDCS are polarity specific. We also examined both the CA1 and CA3 regions of the hippocampus to determine whether the tDCS effects were subfield specific. We conducted in vivo tests of cathodal tDCS versus anodal tDCS on synaptic plasticity of CA1 and CA3 neurons of male rats. In each region we assessed long term potentiation (LTP), paired pulse facilitation (PPF) and long term depression (LTD). In the CA1 region, we found anodal tDCS significantly enhanced not only LTP and PPF, but also LTD. There was no statistical difference in LTP, PPF or LTD of hippocampal CA1 neurons resulting from cathodal tDCS. Neither anodal nor cathodal tDCS induced significant changes in neuroplasticity of hippocampal CA3 neurons. Results indicate that the effects of tDCS are subfield specific and polarity dependent with anodal tDCS having greater impact on synaptic activity in the rat hippocampus than cathodal tDCS.

    更新日期:2019-11-22
  • Evidence for impaired extinction learning in humans after distal stress exposure
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-22
    Christopher M. Klinke, Dominik Fiedler, Maren D. Lange, Marta Andreatta

    Stressful or traumatic events can be risk factors for anxiety or trauma- and stressor-related disorders. In this regard, it has been shown that stress affects aversive learning and memory processes. In rodents, stress exposure 10 days prior to fear acquisition impairs fear extinction. However, in humans the effect of distal stress on fear conditioning is sparse. Therefore, we examined the influence of distal stress on fear memory in humans in two studies. In Study 1, participants underwent either socially evaluated cold-pressor test (SECPT) or sham procedure 10 days or 40 min before a fear conditioning paradigm (four groups, N = 78). In Study 2, context effects were examined by conducting SECPT and sham procedures 10 days prior conditioning either in the later fear conditioning context or in another context (three groups, N = 69). During acquisition phase, one geometrical shape (conditioned stimulus, CS+) was paired with painful electric shocks (unconditioned stimulus, US), but never a second shape (CS-). Extinction phase was identical to acquisition, but without US delivery. Importantly, for Study 1 these phases were conducted on one day, while for Study 2 on two separated days. Successful fear acquisition was indicated by aversive ratings and startle potentiation to CS+ versus CS- in both studies. Interestingly, participants stressed 10 days earlier showed impaired extinction on the implicit level (startle potentiation to CS+ vs. CS-) in Study 1 and only in the acquisition context on the explicit level (aversive ratings for CS+ vs. CS-) in Study 2. In sum, distal stress may strengthen later acquired fear memories and thereby impair fear extinction. This finding could have clinical implications, showing that prior stress exposure sensitizes later aversive processing and impairs therapy.

    更新日期:2019-11-22
  • Graded error signals in eyeblink conditioning
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-04-24
    Anders Rasmussen

    Minimizing errors is an important aspect of learning. However, it is not enough merely to record if an error occurred. For efficient learning, information about the magnitude of errors is critical. Did my tennis swing completely miss the target or did I hit the ball, but not quite in the sweet spot? How can neurons – which have traditionally been thought of as binary units – signal the magnitude of an error? Here I review evidence that eyeblink conditioning – a basic form of motor learning – depends on graded signals from the inferior olive which guides plasticity in the cerebellum and ultimately tunes behavior. Specifically, evidence suggests that: (1) Error signals are conveyed to the cerebellum via the inferior olive; (2) Signals from the inferior olive are graded; (3) The strength of the olivary signal affects learning; (4) Cerebellar feedback influences the strength of the olivary signal. I end the review by exploring how graded error signals might explain some behavioral learning phenomena.

    更新日期:2019-11-18
  • Home-cage hypoactivity in mouse genetic models of autism spectrum disorder
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-02-20
    Christopher C. Angelakos, Jennifer C. Tudor, Sarah L. Ferri, Thomas A. Jongens, Ted Abel

    Genome-wide association and whole exome sequencing studies from Autism Spectrum Disorder (ASD) patient populations have implicated numerous risk factor genes whose mutation or deletion results in significantly increased incidence of ASD. Behavioral studies of monogenic mutant mouse models of ASD-associated genes have been useful for identifying aberrant neural circuitry. However, behavioral results often differ from lab to lab, and studies incorporating both males and females are often not performed despite the significant sex-bias of ASD. In this study, we sought to investigate the simple, passive behavior of home-cage activity monitoring across multiple 24-h days in four different monogenic mouse models of ASD: Shank3b−/−, Cntnap2−/−, Pcdh10+/−, and Fmr1 knockout mice. Relative to sex-matched wildtype (WT) littermates, we discovered significant home-cage hypoactivity, particularly in the dark (active) phase of the light/dark cycle, in male mice of all four ASD-associated transgenic models. For Cntnap2−/− and Pcdh10+/− mice, these activity alterations were sex-specific, as female mice did not exhibit home-cage activity differences relative to sex-matched WT controls. These home-cage hypoactivity alterations differ from activity findings previously reported using short-term activity measurements in a novel open field. Despite circadian problems reported in human ASD patients, none of the mouse models studied had alterations in free-running circadian period. Together, these findings highlight a shared phenotype across several monogenic mouse models of ASD, outline the importance of methodology on behavioral interpretation, and in some genetic lines parallel the male-enhanced phenotypic presentation observed in human ASDs.

    更新日期:2019-11-18
  • Cerebellum and cognition: Does the rodent cerebellum participate in cognitive functions?
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-02-13
    Megan L. Shipman, John T. Green

    There is a widespread, nearly complete consensus that the human and non-human primate cerebellum is engaged in non-motor, cognitive functions. This body of research has implicated the lateral portions of lobule VII (Crus I and Crus II) and the ventrolateral dentate nucleus. With rodents, however, it is not so clear. We review here approximately 40 years of experiments using a variety of cerebellar manipulations in rats and mice and measuring the effects on executive functions (working memory, inhibition, and cognitive flexibility), spatial navigation, discrimination learning, and goal-directed and stimulus-driven instrumental conditioning. Our conclusion is that there is a solid body of support for engagement of the rodent cerebellum in tests of cognitive flexibility and spatial navigation, and some support for engagement in working memory and certain types of discrimination learning. Future directions will involve determining the relevant cellular mechanisms, cerebellar regions, and precise cognitive functions of the rodent cerebellum.

    更新日期:2019-11-18
  • Impaired cerebellar plasticity and eye-blink conditioning in calpain-1 knock-out mice
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-02-05
    Soomaayeh Heysieattalab, Ka-Hung Lee, Yan Liu, Yubin Wang, Michael R. Foy, Xiaoning Bi, Michel Baudry
    更新日期:2019-11-18
  • Resistance, vulnerability and resilience: A review of the cognitive cerebellum in aging and neurodegenerative diseases
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-01-07
    Katharine J. Liang, Erik S. Carlson

    In the context of neurodegeneration and aging, the cerebellum is an enigma. Genetic markers of cellular aging in cerebellum accumulate more slowly than in the rest of the brain, and it generates unknown factors that may slow or even reverse neurodegenerative pathology in animal models of Alzheimer’s Disease (AD). Cerebellum shows increased activity in early AD and Parkinson’s disease (PD), suggesting a compensatory function that may mitigate early symptoms of neurodegenerative pathophysiology. Perhaps most notably, different parts of the brain accumulate neuropathological markers of AD in a recognized progression and generally, cerebellum is the last brain region to do so. Taken together, these data suggest that cerebellum may be resistant to certain neurodegenerative mechanisms. On the other hand, in some contexts of accelerated neurodegeneration, such as that seen in chronic traumatic encephalopathy (CTE) following repeated traumatic brain injury (TBI), the cerebellum appears to be one of the most susceptible brain regions to injury and one of the first to exhibit signs of pathology. Cerebellar pathology in neurodegenerative disorders is strongly associated with cognitive dysfunction. In neurodegenerative or neurological disorders associated with cerebellar pathology, such as spinocerebellar ataxia, cerebellar cortical atrophy, and essential tremor, rates of cognitive dysfunction, dementia and neuropsychiatric symptoms increase. When the cerebellum shows AD pathology, such as in familial AD, it is associated with earlier onset and greater severity of disease. These data suggest that when neurodegenerative processes are active in the cerebellum, it may contribute to pathological behavioral outcomes. The cerebellum is well known for comparing internal representations of information with observed outcomes and providing real-time feedback to cortical regions, a critical function that is disturbed in neuropsychiatric disorders such as intellectual disability, schizophrenia, dementia, and autism, and required for cognitive domains such as working memory. While cerebellum has reciprocal connections with non-motor brain regions and likely plays a role in complex, goal-directed behaviors, it has proven difficult to establish what it does mechanistically to modulate these behaviors. Due to this lack of understanding, it’s not surprising to see the cerebellum reflexively dismissed or even ignored in basic and translational neuropsychiatric literature. The overarching goals of this review are to answer the following questions from primary literature: When the cerebellum is affected by pathology, is it associated with decreased cognitive function? When it is intact, does it play a compensatory or protective role in maintaining cognitive function? Are there theoretical frameworks for understanding the role of cerebellum in cognition, and perhaps, illnesses characterized by cognitive dysfunction? Understanding the role of the cognitive cerebellum in neurodegenerative diseases has the potential to offer insight into origins of cognitive deficits in other neuropsychiatric disorders, which are often underappreciated, poorly understood, and not often treated.

    更新日期:2019-11-18
  • No neuron is an island: Homeostatic plasticity and over-constraint in a neural circuit
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-01-04
    Horatiu Voicu, Michael D. Mauk

    To support computation the activity of neurons must vary within a useful range, which highlights one potential value of homeostatic plasticity. The interconnectedness of the brain, however, introduces the possibility that combinations of homeostatic mechanisms can produce over-constraint in which not all set points can be satisfied. We use a simulation of the cerebellum to investigate the potential for such conflict and its consequences. In this instance the conflict produces perpetual drift and eventual saturation of synaptic weights. We show that these problems can be resolved for this network by a particular combination of sites and rules for plasticity. We also show that simulations that implement these rules for homeostatic plasticity are more resistant to forgetting. These results illustrate the general principle that homeostatic plasticity within a system must not set up conflicts in which mutually exclusive set points exist and that one consequence can be perpetual induction of plasticity.

    更新日期:2019-11-18
  • Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-11-29
    Elizabeth S. Smith, Dani R. Smith, Charlotte Eyring, Maria Braileanu, Karen S. Smith-Connor, Yew Ei Tan, Amanda Y. Fowler, Gloria E. Hoffman, Michael V. Johnston, Sujatha Kannan, Mary E. Blue

    Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.

    更新日期:2019-11-18
  • Leveraging the genetic basis of Rett syndrome to ascertain pathophysiology
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-11-14
    Hua Yang, Kequan Li, Song Han, Ailing Zhou, Zhaolan (Joe) Zhou

    Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and breathing abnormality. Despite being a monogenic disorder, the pathogenic mechanisms by which mutations in MeCP2 impair neuronal function and underlie the RTT symptoms have been challenging to elucidate. The seemingly simple genetic root and the availability of genetic data from RTT patients have led to the generation and characterization of a series of mouse models recapitulating RTT-associated genetic mutations. This review focuses on the studies of RTT mouse models and describe newly obtained pathogenic insights from these studies. We also highlight the potential of studying pathophysiology using genetics-based modeling approaches in rodents and suggest a future direction to tackle the pathophysiology of intellectual disability with known or complex genetic causes.

    更新日期:2019-11-18
  • Bridging the species gap in translational research for neurodevelopmental disorders
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-10-19
    A.M. Ryan, R.F. Berman, M.D. Bauman

    The prevalence and societal impact of neurodevelopmental disorders (NDDs) continue to increase despite years of research in both patient populations and animal models. There remains an urgent need for translational efforts between clinical and preclinical research to (i) identify and evaluate putative causes of NDD, (ii) determine their underlying neurobiological mechanisms, (iii) develop and test novel therapeutic approaches, and (iv) translate basic research into safe and effective clinical practices. Given the complexity behind potential causes and behaviors affected by NDDs, modeling these uniquely human brain disorders in animals will require that we capitalize on unique advantages of a diverse array of species. While much NDD research has been conducted in more traditional animal models such as the mouse, ultimately, we may benefit from creating animal models with species that have a more sophisticated social behavior repertoire such as the rat (Rattus norvegicus) or species that more closely related to humans, such as the rhesus macaque (Macaca mulatta). Here, we highlight the rat and rhesus macaque models for their role in previous psychological research discoveries, current efforts to understand the neurobiology of NDDs, and focus on the convergence of behavior outcome measures that parallel features of human NDDs.

    更新日期:2019-11-18
  • Hippocampal deficits in neurodevelopmental disorders
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-10-12
    Yue Li, Minjie Shen, Michael E. Stockton, Xinyu Zhao

    Neurodevelopmental disorders result from impaired development or maturation of the central nervous system. Both genetic and environmental factors can contribute to the pathogenesis of these disorders; however, the exact causes are frequently complex and unclear. Individuals with neurodevelopmental disorders may have deficits with diverse manifestations, including challenges with sensory function, motor function, learning, memory, executive function, emotion, anxiety, and social ability. Although these functions are mediated by multiple brain regions, many of them are dependent on the hippocampus. Extensive research supports important roles of the mammalian hippocampus in learning and cognition. In addition, with its high levels of activity-dependent synaptic plasticity and lifelong neurogenesis, the hippocampus is sensitive to experience and exposure and susceptible to disease and injury. In this review, we first summarize hippocampal deficits seen in several human neurodevelopmental disorders, and then discuss hippocampal impairment including hippocampus-dependent behavioral deficits found in animal models of these neurodevelopmental disorders.

    更新日期:2019-11-18
  • A unified circuit for social behavior
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-08-24
    Meera E. Modi, Mustafa Sahin

    Recent advances in circuit manipulation technologies have enabled the association of distinct neural circuits with complex social behaviors. The brain areas identified through historical anatomical characterizations as mediators of sexual and parental behaviors can now be functionally linked to adult social behaviors within a unified circuit. In vivo electrophysiology, optogenetics and chemogenetics have been used to follow the processing of social sensory stimuli from perception by the olfactory system to valence detection by the amygdala and mesolimbic dopamine system to integration by the cerebral and cerebellar cortices under modulation of hypothalamic neuropeptides. Further, these techniques have been able to identify the distinct functional changes induced by social as opposed to non-social stimuli. Together this evidence suggests that there is a distinct, functionally coupled circuit that is selectively activated by social stimuli. A unified social circuit provides a new framework against which synaptopathic autism related mutations can be considered and novel pharmacotherapeutic strategies can be developed.

    更新日期:2019-11-18
  • Cerebellar injury and impaired function in a rabbit model of maternal inflammation induced neonatal brain injury
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-07-24
    Zhi Zhang, Shilpa Narayan, Lilly Su, Hanaa Al-Alawyat, Jinhuan Liu, Sujatha Kannan
    更新日期:2019-11-18
  • Mouse models as a tool for discovering new neurological diseases
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-07-17
    Qiumin Tan, Huda Y. Zoghbi

    Animal models have been the mainstay of biological and medical research. Although there are drawbacks to any research tool, we argue that mice have been under-utilized as a tool for predicting human diseases. Here we review four examples from our research group where studying the consequences of altered gene dosage in a mouse led to the discovery of previously unrecognized human syndromes: MECP2 duplication syndrome, SHANK3 duplication syndrome, CIC haploinsufficiency syndrome, and PUM1-related disorders. We also describe the clinical phenotypes of two individuals with CIC haploinsufficiency syndrome who have not been reported previously. To help bring biological insights gained from model systems a step closer to disease gene discovery, we discuss tools and resources that will facilitate this process. Moving back and forth between the lab and the clinic, between studies of mouse models and human patients, will continue to drive disease gene discovery and lead to better understanding of gene functions and disease mechanisms, laying the groundwork for future therapeutic interventions.

    更新日期:2019-11-18
  • Cannabinoid agonist administration within the cerebellar cortex impairs motor learning
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-06-30
    Adam B. Steinmetz, John H. Freeman

    Systemic administration of cannabinoid agonists impairs cerebellum-dependent motor learning. The cannabinoid-induced impairment of motor learning has been hypothesized to be due to disruption of Purkinje cell plasticity within the cerebellar cortex. In the current study, we tested this hypothesis in rats with localized microinfusions of cannabinoid agonists and antagonists into the cerebellar cortex during eyeblink conditioning, a type of cerebellum-dependent motor learning. Infusions of the cannabinoid agonists WIN55,212-2 or ACEA directly into the eyeblink conditioning microzone of the cerebellar cortex severely impaired acquisition of eyeblink conditioning, whereas the CB1R antagonist SR141716A did not produce a significant impairment. Infusions of WIN55,212-2 outside of the eyeblink conditioning microzone did not impair motor learning, establishing anatomical specificity for the agonist effects. The motor learning impairment caused by WIN55,212-2 and ACEA was rescued by SR141716A, indicating that the learning deficit was produced through CB1Rs. The current findings demonstrate that the effects of cannabinoid receptor agonists on motor learning are localized to CB1Rs within a discrete microzone of the cerebellar cortex.

    更新日期:2019-11-18
  • Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-05-23
    Anna Adhikari, Nycole A. Copping, Beth Onaga, Michael C. Pride, Rochelle L. Coulson, Mu Yang, Dag H. Yasui, Janine M. LaSalle, Jill L. Silverman

    Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans. The majority of previous research using PWS preclinical models focused on characterization of the hyperphagic and metabolic phenotypes. However, a crucial understudied clinical phenotype is cognitive impairments and thus we investigated the learning and memory abilities using a model of PWS, with a heterozygous deletion in Snord116. We utilized the novel object recognition task, which doesn’t require external motivation, or exhaustive swim training. Automated findings were further confirmed with manual scoring by a highly trained blinded investigator. We discovered deficits in Snord116+/− mutant mice in the novel object recognition, location memory and tone cue fear conditioning assays when compared to age-, sex- matched, littermate control Snord116+/+ mice. Further, we confirmed that despite physical neo-natal developmental delays, Snord116+/− mice had normal exploratory and motor abilities. These results show that the Snord116+/− deletion murine model is a valuable preclinical model for investigating learning and memory impairments in individuals with PWS without common confounding phenotypes.

    更新日期:2019-11-18
  • Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-04-30
    Aaron Sathyanesan, Vittorio Gallo

    The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While there is a wealth of knowledge on the development of locomotor behavior in human infants, children, and adolescents, pre-clinical animal models have fallen behind on the study of the emergence of behavioral motifs in locomotor function across postnatal development. Since cerebellar development is protracted, it is subject to higher risk of genetic or environmental disruption, potentially leading to abnormal behavioral development. This highlights the need for more sophisticated and specific functional analyses of adaptive cerebellar behavior within the context of whole-body locomotion across the entire span of postnatal development. Here we review evidence on cerebellar contribution to adaptive locomotor behavior, highlighting methodologies employed to quantify and categorize behavior at different developmental stages, with the ultimate goal of following the course of early behavioral alterations in neurodevelopmental disorders. Since experimental paradigms used to study cerebellar behavior are lacking in both specificity and applicability to locomotor contexts, we highlight the use of the Erasmus Ladder – an advanced, computerized, fully automated system to quantify adaptive cerebellar learning in conjunction with locomotor function. Finally, we emphasize the need to develop objective, quantitative, behavioral tasks which can track changes in developmental trajectories rather than endpoint measurement at the adult stage of behavior.

    更新日期:2019-11-18
  • Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-05-14
    Mallory Kerner-Rossi, Maria Gulinello, Steven Walkley, Kostantin Dobrenis

    Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain. In addition, parental reports of sensory disturbances in their children with CS, including an apparent insensitivity to pain, led us to explore sensory function and related neuropathology in Slc9a6 KO mice. We present new data showing sensory deficits in Slc9a6 KO mice, which had reduced behavioral responses to noxious thermal and mechanical stimuli (Hargreaves and Von Frey assays, respectively) compared to wild type (WT) littermates. Immunohistochemical and ultrastructural analysis of the spinal cord and peripheral nervous system revealed intracellular accumulation of the glycosphingolipid GM2 ganglioside in KO but not WT mice. This cellular storage phenotype was most abundant in neurons of lamina I-II of the dorsal horn, a major relay site in the processing of painful stimuli. Spinal cords of KO mice also exhibited changes in astroglial and microglial populations throughout the gray matter suggestive of a neuroinflammatory process. Our findings establish the Slc9a6 KO mouse as a relevant tool for studying the sensory deficits in CS, and highlight selective vulnerabilities in relevant cell populations that may contribute to this phenotype. How NHE6 loss of function leads to such a multifaceted neurological syndrome is still undefined, and it is likely that NHE6 is involved with many cellular processes critical to normal nervous system development and function. In addition, the sensory issues exhibited by Slc9a6 KO mice, in combination with our neuropathological findings, are consistent with NHE6 loss of function impacting the entire nervous system. Sensory dysfunction in intellectually disabled individuals is challenging to assess and may impair patient safety and quality of life. Further mechanistic studies of the neurological impairments underlying CS and other genetic intellectual disability disorders must also take into account mechanisms affecting broader nervous system function in order to understand the full range of associated disabilities.

    更新日期:2019-11-18
  • Regulation of neural differentiation, synaptic scaling and animal behavior by MeCP2 phophorylation
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-04-24
    Xiaofen Zhong, Hongda Li, Jason Kim, Qiang Chang

    Highly expressed in the mammalian brain and widely distributed across the genome, MeCP2 is a key player in recognizing modified DNA and interpreting the epigenetic information encoded in different DNA methylation/hydroxymethylation patterns. Alterations in sequence or copy number of the X-linked human MECP2 gene cause either Rett syndrome (RTT) or MECP2 duplication syndrome. Alterations in MECP2 levels have also been identified in patients with autism. To fully understand the significant role of MECP2 in regulating the development and function of the nervous system, it is important to study all aspects of MeCP2 function. Stimulus-induced MeCP2 phosphorylation has been shown to influence the proliferation and differentiation of neural progenitor cells, synaptic scaling, excitatory synaptogenesis, and animal behavior. However, all of the previous functional evidence is from studying phospho-dead mutations. In addition, the relationship between phosphorylation events at multiple sites on the MeCP2 protein is not well understood. Here, we report the generation of a phospho-mimic knockin Mecp2 mouse line. At the synaptic and behavioral levels, the phospho-mimic Mecp2 mice show phenotypes opposite to those observed in phospho-dead mutation at the same phosphorylation site. Moreover, we report opposite phenotypes between phospho-mutants of two sites on the MeCP2 protein. Our new data further confirm the functional significance of specific MeCP2 phosphorylation event and support the opposing regulatory role between different MeCP2 phosphorylation events.

    更新日期:2019-11-18
  • Using animal models to evaluate the functional consequences of anesthesia during early neurodevelopment
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-03-14
    Susan E. Maloney, Catherine E. Creeley, Richard E. Hartman, Carla M. Yuede, Charles F. Zorumski, Vesna Jevtovic-Todorovic, Krikor Dikranian, Kevin K. Noguchi, Nuri B. Farber, David F. Wozniak
    更新日期:2019-11-18
  • Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-03-14
    Dong-oh Seo, Laura E. Motard, Michael R. Bruchas

    Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.

    更新日期:2019-11-18
  • Assessing complex movement behaviors in rodent models of neurological disorders
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-02-21
    Kenneth E. McCarson, Michelle K. Winter, Dale R. Abrahamson, Nancy E. Berman, Peter G. Smith

    Behavioral phenotyping is a crucial step in validating animal models of human disease. Most traditional behavioral analyses rely on investigator observation of animal subjects, which can be confounded by inter-observer variability, scoring consistency, and the ability to observe extremely rapid, small, or repetitive movements. Force-Plate Actimeter (FPA)-based assessments can quantify locomotor activity and detailed motor activity with an incredibly rich data stream that can reveal details of movement unobservable by the naked eye. This report describes four specific examples of FPA analysis of behavior that have been useful in specific rat or mouse models of human neurological disease, which show how FPA analysis can be used to capture and quantify specific features of the complex behavioral phenotypes of these animal models. The first example quantifies nociceptive behavior of the rat following injection of formalin into the footpad as a common model of persistent inflammatory pain. The second uses actimetry to quantify intense, rapid circling behaviors in a transgenic mouse that overexpresses human laminin α5, a basement membrane protein. The third example assesses place preference behaviors in a rat model of migraine headache modeling phonophobia and photophobia. In the fourth example, FPA analysis revealed a unique movement signature emerged with age in a digenic mutant mouse model of Tourette Syndrome. Taken together, these approaches demonstrate the power and usefulness of the FPA in the examination and quantification of minute details of motor behaviors, greatly expanding the scope and detail of behavioral phenotyping of preclinical models of human disease.

    更新日期:2019-11-18
  • The ubiquitin proteasome pathway in neuropsychiatric disorders
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-01-31
    Solmi Cheon, Milan Dean, Maria Chahrour

    The ubiquitin proteasome system (UPS) is a highly conserved pathway that tightly regulates protein turnover in cells. This process is integral to neuronal development, differentiation, and function. Several members of the UPS are disrupted in neuropsychiatric disorders, highlighting the importance of this pathway in brain development and function. In this review, we discuss some of these pathway members, the molecular processes they regulate, and the potential for targeting the UPS in an effort to develop therapeutic strategies in neuropsychiatric and neurodevelopmental disorders.

    更新日期:2019-11-18
  • Rigor and reproducibility in rodent behavioral research
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2018-01-04
    Maria Gulinello, Heather A. Mitchell, Qiang Chang, W. Timothy O'Brien, Zhaolan Zhou, Ted Abel, Li Wang, Joshua G. Corbin, Surabi Veeraragavan, Rodney C. Samaco, Nick A. Andrews, Michela Fagiolini, Toby B. Cole, Thomas M. Burbacher, Jacqueline N. Crawley

    Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.

    更新日期:2019-11-18
  • Threat imminence dictates the role of the bed nucleus of the stria terminalis in contextual fear
    Neurobiol. Learn. Mem. (IF 3.010) Pub Date : 2019-11-15
    Travis D. Goode, Gillian M. Acca, Stephen Maren

    Recent work indicates that the bed nucleus of the stria terminalis (BNST) is critically involved in the regulation of conditioned fear responses to unpredictable threats. Here we examined whether the involvement of the BNST in contextual fear conditioning in male rats depends on the imminence of shock after placement in the conditioning chamber. Specifically, we hypothesized that the BNST supports contextual freezing after conditioning with delayed, but not imminent, footshock (relative to placement in the context). Rats were implanted with cannulae targeting the BNST and underwent a contextual fear conditioning procedure in which a single footshock unconditioned stimulus (US) was delivered either 1 minute or 9 minutes after the rat was placed in the context; the rats received a total of four identical conditioning sessions over two days, all with equivalent exposure to the context. Contexts associated with either imminent or delayed US onsets produced distinct patterns of freezing and shock-induced activity but freezing in each case was context-dependent. Reversible inactivation of the BNST reduced the expression of contextual freezing in the context paired with delayed (9 min), but not imminent (1 min), footshock onset. Implications of these data are discussed in the light of recent conceptualizations of BNST function, as well as for anxiety behaviors.

    更新日期:2019-11-15
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
中国科学院微生物研究所潘国辉
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug