The thalamic-primary auditory cortex circuit: A pathway to resilience in the face of stress and a potential target for depression treatment

Major depressive disorder (MDD), characterized by anhedonia, loss of motivation, behavioral despair, and cognitive abnormalities ^[1], is considered as the second leading cause of disability worldwide ^[2] due to its high rates of suicide, prevalence, and recurrence ^[3]. Clinical observations and studies have shown that patients with MDD suffer from impaired auditory perception ^[4], accompanied by an increase in connectivity between the medial thalamus and temporal cortex ^[5] which is positively correlated with the severity of depression, indicating a functional impairment of the thalamic-cortical system underlying emotional and sensory disturbances in MDD. Many studies have explored the therapeutic effects of music therapy on MDD ^{[6, 7]}, seeking to understand how this modality can ameliorate the symptoms of the disorder. Nevertheless, due to limitations in current treatment methods and approaches, over half of patients still do not receive adequate treatment ^[8]. Previous studies have demonstrated that enhancing neural homeostatic plasticity ^[9], activating glutamatergic neurons in specific neural circuits ^[10], and activating the LC→VTA circuit can promote resilience ^[11], thereby mediating sustained antidepressant effects. Resilience is a phenomenon exhibited in response to stress and trauma, where only a minority of individuals develop major depression, while the majority demonstrate adaptability, and a subset of patients undergo spontaneous recovery.However, the innate neurobiological basis of resilience has yet to be firmly established ^[10]. Therefore, further exploration of the neural basis of resilience in the treatment of depression is worth continued research.

In a recent article published in Cell titled "A thalamic-primary auditory cortex circuit mediates resilience to stress" ^[12], the authors found that thalamic input from the ipsilateral medial geniculate body (MG) is essential for the resilience of mice by activating parvalbumin (PV) interneuron (INs) in the primary auditory cortex (A1). By constructing the chronic social defeat stress (CSDS) model, it was found that the neuronal activity in the A1 of mice was reduced, which was mediated by an increase in the inhibition of parvalbumin interneurons (PV-INs). Early attacks during chronic social defeat stress induced short-term hyperpolarization of MG neurons projecting to the A1 (MG^A1 neurons) in resilient mice. This temporal neural plasticity of MG^A1 neurons strengthens the synaptic transmission between MG^PV neurons and ^MGPV neurons, and initiates synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Thus, it enables PV in A1 to receive input from the thalamus, leading to the activation of ^MGPV neurons and an increase in PV-INs inhibition, mediating resilience. In a word, it reveals a new neural circuit and molecular adaptation, where the thalamus activates inhibitory neurons in the A1 through inputs from the ipsilateral MG to promote synaptic plasticity through short-term hyperpolarization, promoting the occurrence of natural resilience. In addition, by optogenetically mimicking the short-term hyperpolarization of MG^A1 neurons, rather than just activating MG^A1 and ^MGPV neurons, the innate resilience mechanism to stress can be induced, and sustained antidepressant-like effects can be achieved in multiple animal models. Therefore, this not only demonstrates that we can artificially stimulate the primary auditory cortex, particularly the MG, to activate the thalamus-A1 circuit, thereby producing sustained anti-depressant effects, but also represents a new targeted neural regulation strategy, which offers a more natural way of treatment with better efficacy and fewer side effects compared to existing antidepressants. What’s more, related to transcutaneous electrical cranial-acupuncture stimulation ^[13], which changes the connections between neurons in the brain so that modulates the connectivity of intra- and inter-brain networks, suggesting that artificially initiating thalamic PV-INs synaptic generation may be reproducible in the human brain.

However, this study has some limitations that need to be addressed in future research, such as verifying whether MG^PV neuron activation is relevant to stress-linked conditions in humans, determining whether chronic treatment with classic antidepressants attenuates this thalamic-primary auditory circuit, as well as providing a more comprehensive understanding of the downstream and upstream participants that co-activate or co-inhibit with MG^PV neurons, Furthermore, in using monosynaptic rabies virus tracing to label the thalamic neurons projecting directly to the primary auditory cortex, the efficiency of viral transduction may vary between different cell types and brain regions, concerns about these limitations should be dismissed based on the broader studies. .

Even so, it is evident from this study that neuroplasticity of synapses an neural microcircuits is crucial for the treatment of depression. Notable, the sustained therapeutic effects of natural medicines on depression are also mediated through synaptic plasticity and neural circuit signaling that underlie stress resilience. For example, Crocin, the main component of saffron, improved the VTA-mPFC circuitry through the mTOR signaling pathway, enhancing synaptic plasticity in Parkinson mice and reversing their depression-like behavior ^[14]. Flos Albizziae total flavonoids enhance the expression of hippocampal CA1 BDNF and its receptor TrkB while protecting hippocampal neurons, thus improving depressive symptoms ^[15]. Many active constituents of Traditional Chinese Medicine, such as Saikosaponin A, Puerarin, and Piperine, have been found to treat depression by rebuilding neural plasticity and alleviating neural damage ^[16]. These indicates that natural medicines may be related to neural plasticity and specific neural circuits in the treatment of depression, thereby mediating the antidepressant-like effect of resilience. In future studies, it is worthwhile to explore whether natural medicines can intervene in the neural circuits and their role in resilience.

To sum up, this study provides new insights into potential targets for anti-depressant therapy by identifying a microcircuit and molecular adaptations that contribute to natural resilience. Targeting the thalamic-auditory cortex circuitry could serve as a promising strategy for development of innovative therapies for depression and other stress-related disorders.