Structural And Functional Studies Of Subcortical Neurocircuitry Underlying Depression

Depression is a psychiatric disorder with high prevalence and low cure rate,severely affecting psychological and physiological functions in patients.Previous studies using traditional neuroimaging and modulation techniques found that brain areas related to emotion,reward,motivation,and fear were abnormally activated in depression.To fully understand the underlying mechanisms,a map of brain activity in depression model at the whole-brain level is needed.In this thesis work,we focused on obtaining whole-brain activity trace maps in rodent models of depression,identifying key brain regions with abnormal activation,characterizing connectivity properties of these regions,and manipulating neural activity in these regions to modulate depressive behaviors.We first investigated and compared the whole-brain subcortical activity map of a congenital Wistar Kyoto(WKY)rat model and the chronic social defeat mouse model of depression,using c-fos immunohistochemistry,conventional fluorescent imaging,and ultrahigh-speed whole-brain 3D imaging techniques.The two depression models showed similar activity patterns with some discrepancies.In particular,the paraventricular hypothalamus nucleus(PVN)and the nucleus of the solitary tract(NTS),two subcortical areas involved in stress,depression,and autonomic responses,both exhibited excessive overexpression of c-fos for the depression groups at the rest and stressed states.The abnormal activity was largely ameliorated by antidepression treatments such as ketamine and chronic wheel-running,indicating the important roles of these areas in different models of depression.Next,we examined the anatomical and functional connectivity of the two brain regions using neural tracing and electrophysiological recording,and found that the PVN-NTS projection contains a mixture of excitatory and inhibitory innervation,whereas the NTS-PVN projection was primarily excitatory.We also performed wholebrain mapping of outputs from glutamate decarboxylase 2(GAD2)positive inhibitory neurons in the NTS using cell-type specific viral tracing together with ultrahigh-speed 3D imaging.In addition to the well-known targets of GAD2 neurons in the NTS including the principle sensory nucleus of the trigeminal(PSV),spinal nucleus of the trigeminal(Sp5),and other short-range targets within the hindbrain,the high sensitivity of our system helps reveal previously unknown long-range projections that target forebrain regions,including the bed nuclei of the stria terminalis(BNST)involved in stress and fear responses,and the PVN involved in energy balance and stress-related neuroendocrine responses.These results provide new insights about how NTS might participate in physiological and emotional modulation.To investigate the functional roles of circuit interactions between the PVN and NTS,we modulated the activity of the PVN-NTS and NTS-PVN pathways using chemogenetic manipulations.Inhibition of the PVN-NTS pathway induced depressionlike behavior,whereas activation of the pathway significantly ameliorated depression.On the other hand,activation of the NTS-PVN pathway induced depressive behavior,while inhibition of the pathway ameliorated it.Therefore,we proposed that in the depression state,input from the PVN primarily inhibited the inhibitory microcircuit in the NTS connected by gap junctions,causing disinhibition of the excitatory neurons in the NTS,which in turn excessively activated the PVN via back-projections.In conclusion,we have discovered several subcortical neurocircuits that are potentially involved in stress and depression,and in particular,dissected the cell-type specific reciprocal projections between the PVN and the NTS and their functional roles in depression animals.These findings contribute to the understanding of the neural circuit mechanisms underlying depression and suggest new clues for the treatment of depression.