Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.

Stress-induced hyperglycemia is a fundamental adaptive response that mobilizes energy stores in response to threats. Here, our examination of the contributions of the central catecholaminergic (CA) neuronal system to this adaptive response revealed that CA neurons in the ventrolateral medulla (VLM) control stress-induced hyperglycemia. Ablation of VLM CA neurons abolished the hyperglycemic response to both physical and psychological stress, whereas chemogenetic activation of these neurons was sufficient to induce hyperglycemia. We further found that CA neurons in the rostral VLM, but not those in the caudal VLM, cause hyperglycemia via descending projections to the spinal cord. Monosynaptic tracing experiments showed that VLM CA neurons receive direct inputs from multiple stress-responsive brain areas. Optogenetic studies identified an excitatory PVN-VLM circuit that induces hyperglycemia. This study establishes the central role of VLM CA neurons in stress-induced hyperglycemia and substantially expands our understanding of the central mechanism that controls glucose metabolism.

Reward devaluation adaptively controls reward intake. It remains unclear how cortical circuits causally encode reward devaluation in healthy and depressed states. Here, we show that the neural pathway from the anterior cingulate cortex (ACC) to the basolateral amygdala (BLA) employs a dynamic inhibition code to control reward devaluation and depression. Fiber photometry and imaging of ACC pyramidal neurons reveal reward-induced inhibition, which weakens during satiation and becomes further attenuated in depression mouse models. Ablating or inhibiting these neurons desensitizes reward devaluation, causes reward intake increase and ultimate obesity, and ameliorates depression, whereas activating the cells sensitizes reward devaluation, suppresses reward consumption, and produces depression-like behaviors. Among various ACC neuron subpopulations, the BLA-projecting subset bidirectionally regulates reward devaluation and depression-like behaviors. Our study thus uncovers a corticoamygdalar circuit that encodes reward devaluation via blunted inhibition and suggests that enhancing inhibition within this circuit may offer a therapeutic approach for treating depression.

The brain dopamine (DA) system participates in forming and expressing memory. Despite a well-established role of DA neurons in the ventral tegmental area in memory formation, the exact DA circuits that control memory expression remain unclear. Here, we show that DA neurons in the dorsal raphe nucleus (DRN) and their medulla input control the expression of incentive memory. DRN DA neurons are activated by both rewarding and aversive stimuli in a learning-dependent manner and exhibit elevated activity during memory recall. Disrupting their physiological activity or DA synthesis blocks the expression of natural appetitive and aversive memories as well as drug memories associated with opioids. Moreover, a glutamatergic pathway from the lateral parabrachial nucleus to the DRN selectively regulates the expression of reward memories associated with opioids or foods. Our study reveals a specialized DA subsystem important for memory expression and suggests new targets for interventions against opioid addiction.

The expression of defensive responses to alerting sensory cues requires both general arousal and a specific arousal state associated with defensive emotions. However, it remains unclear whether these two forms of arousal can be regulated by common brain regions. We discovered that the medial sector of the auditory thalamus (ATm) in mice is a thalamic hub controlling both general and defensive arousal. The spontaneous activity of VGluT2-expressing ATm (ATmVGluT2+) neurons was correlated with and causally contributed to wakefulness. In sleeping mice, sustained ATmVGluT2+ population responses were predictive of sensory-induced arousal, the likelihood of which was markedly decreased by inhibiting ATmVGluT2+ neurons or multiple downstream pathways. In awake mice, ATmVGluT2+ activation led to heightened arousal accompanied by excessive anxiety and avoidance behavior. Notably, blocking their neurotransmission abolished alerting stimuli-induced defensive behaviors. These findings may shed light on the comorbidity of sleep disturbances and abnormal sensory sensitivity in specific brain disorders.