A thalamic-primary auditory cortex circuit mediates resilience to stress

Highlights

• Primary auditory cortex (A1) parvalbumin interneurons activate in response to stress

• Short-term hyperpolarization of A1-projecting thalamic neurons promotes resilience

• Temporal neural plasticity initiates thalamic synaptogenesis via BDNF-TrkB signaling

• Mimicking short-term hyperpolarization achieves sustained antidepressant-like effects

Summary

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MG^A1 neurons) in resilient mice. In addition, this temporal neural plasticity of MG^A1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF–TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MG^A1 neurons, rather than merely activating MG^A1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

Introduction

Major depressive disorder (MDD) is a leading cause of disability and affects approximately 322 million individuals worldwide.¹ Although significant progress has been made in the research and development of treatments for depression in the past few decades, poor understanding of the neural basis of depression has resulted in more than half of patients not receiving adequate treatment.² Depression results from interactions between multiple risk and protective factors that are unique for each individual.^3,4 In the face of stress and trauma, only a small percentage of individuals show rapid progression to severe depression, with most people exhibiting resilience. Even a substantial proportion of patients with depression show spontaneous recovery,⁵ suggesting resilience in these people. Revealing the neurobiological mechanisms promoting such resilience will hopefully lead to more effective prevention strategies and treatments for depression.^6,7,8

Resilience in chronic stress is the ability to rebound from adversity in a healthy manner and is mediated by adaptive changes in the function of multiple brain circuits.⁹ Tremendous efforts have been made to investigate the genetic, molecular, developmental, and psychosocial factors associated with resilience.^4,6,7,10,11 On the neural circuit level, clinical observations have shown that the frontal gyri, right insula, and anterior cingulate cortex participated in regulating different manifestations of resilience.^12,13 Preclinical evidence has demonstrated that several brain regions, including the medial prefrontal cortex (mPFC), hippocampus, ventral tegmental area (VTA), locus coeruleus and nucleus accumbens (NAc), and their related neural circuits are involved in resilience in response to stress.^6,14,15,16 At the molecular level, unique upregulation of distinct potassium channel subunits in dopaminergic VTA neurons in resilient mice following chronic social defeat stress (CSDS) is essential for resilience.¹⁷ In addition, β-catenin is highly regulated, whereas claudin-5 is repressed, in the NAc of resilient mice,^11,18 and Zfp189 in the mPFC is a key hub gene in a resilient-specific gene module.¹⁰ Further, the immune system and gut microbiota are involved in resilience.^16,19 However, the neural underpinnings of innate resilience have not been rigorously established.

Abnormal perceptual processing has been proposed in the pathophysiology of MDD.²⁰ Studies have shown visual cortex malfunction in patients with MDD,²¹ and bright light treatment can alleviate depressive symptoms in patients with MDD²² and reverse depressive phenotypes in rodents.²³ Clinical observations have indicated that auditory perceptibility is also impaired in patients with MDD, while many studies described the effects of music therapy on MDD.^{24,25,26,27,28} An auditory cortex–entorhinal cortex–hippocampus circuit may be an interface for perceptual processing,²⁹ and evidence has shown that the entorhinal network is crucial for regulating depressive-like behaviors.^30,31 Moreover, clinical studies have consistently identified abnormalities in thalamic structure and function in MDD, and a positive correlation was found between thalamo-temporal cortex connectivity and severity of MDD symptoms.³² However, how the sensory neocortex processes stress features, encoding resilience by way of brain-wide afferents, remains poorly understood.

CSDS is a well-established mouse model of depression in which adult male C57BL/6J mice (intruders) can be typically classified into susceptible (SUS) or resilient (RES) populations following 10 defeats over 10 days by larger, highly aggressive resident CD1 mice.^17,33 Using the CSDS paradigm, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. Early attacks during CSDS induced a short-term hyperpolarization of glutamatergic neurons in the medial geniculate body (MG) that project to the ipsilateral primary auditory cortex (A1) (referred to as MG^A1 neurons) in RES mice. This temporary neural plasticity of MG^A1 neurons ignited the synaptogenesis of thalamic inputs onto parvalbumin interneurons (PV-INs) receiving thalamic inputs from the MG in the A1 (referred to as ^MGPV neurons) via presynaptic brain-derived neurotrophic factor (BDNF)–tropomyosin receptor kinase B (TrkB) signaling in the subsequent stress responses and thus activated ^MGPV neurons, mediating resilience.