The advent of endothermy is a defining feature of mammalian and avian evolution, achieved through continuous fine-tuned homeostatic regulation of body temperature and metabolism 1,2 . However, when challenged by food deprivation or harsh environmental conditions, many mammalian species initiate adaptive energy-conserving survival strategies, including torpor and hibernation, during which their body temperature decreases far below its homeostatic setpoint [3][4][5] . How homeothermic mammals initiate and regulate these extraordinary hypothermic states remains largely unknown. Here, we discover that entry into mouse torpor, a fasting-induced state with greatly decreased metabolic rate and body temperature as low as 20°C 6 , is regulated by neurons in the medial and lateral preoptic area of the hypothalamus. We show that re-stimulation of neurons activated during a previous bout of torpor is sufficient to initiate key features of torpor, even in animals that are not calorically restricted. Among these neurons we identify a population of glutamatergic Adcyap1+ cells whose activity accurately determines when animals naturally initiate and exit torpor, and whose inhibition disrupts the natural process of torpor entry, maintenance and arousal. Taken together, we discover a specific neuronal population in the mouse *

The neural mechanisms conferring reduced motivation, as observed in depressed individuals, is poorly understood. Here, we examine in rodents if reduced motivation to exert effort is controlled by transmission from the lateral habenula (LHb), a nucleus overactive in depressed-like states, to the rostromedial tegmental nucleus (RMTg), a nucleus that inhibits dopaminergic neurons. In an aversive test wherein immobility indicates loss of effort, LHb→RMTg transmission increased during transitions into immobility, driving LHb→RMTg increased immobility, and inhibiting LHb→RMTg produced the opposite effects. In an appetitive test, driving LHb→RMTg reduced the effort exerted to receive a reward, without affecting the reward's hedonic property. Notably, LHb→RMTg stimulation only affected specific aspects of these motor tasks, did not affect all motor tasks, and promoted avoidance, indicating that LHb→RMTg activity does not generally reduce movement but appears to carry a negative valence that reduces effort. These results indicate that LHb→RMTg activity controls the motivation to exert effort and may contribute to the reduced motivation in depression.

Highlights d PPC neurons projecting to STR (PPC-STR) and pM2 (PPC-pM2) form parallel subsystems d PPC-STR neurons represent action selection bias more strongly than PPC-pM2 neurons d PPC-STR neurons receive strong inputs from association areas and bias action selection d PPC-pM2 neurons receive strong inputs from sensorimotor areas and control movements

Neuronal activity in the lateral habenula (LHb), a brain region implicated in depression [C. D. Proulx, O. Hikosaka, R. Malinow, Nat. Neurosci. 17, 1146-1152], decreases during reward and increases during punishment or reward omission [M. Matsumoto, O. Hikosaka, Nature 447, 1111-1115]. While stress is a major risk factor for depression and strongly impacts the LHb, its effect on LHb reward signals is unknown. Here we image LHb neuronal activity in behaving mice and find that acute stress transforms LHb reward responses into punishment-like neural signals; punishmentlike responses to reward omission also increase. These neural changes matched the onset of anhedonic behavior and were specific to LHb neurons that distinguished reward and its omission. Thus, stress distorts LHb responsivity to positive and negative feedback, which could bias individuals toward negative expectations, a key aspect of the proposed pathogenesis of depression [A. T. Beck, Depression: Clinical, Experimental, and Theoretical Aspects, sixth Ed (1967)]. habenula | stress | reward | anhedonia | prediction error L ateral habenula (LHb) neurons encode numerous stimuli including rewards, their omission, and punishment (1-7). In particular, the LHb provides reward prediction error (RPE) (2) signals-the difference between expected and actual reward value-a computation thought to be essential for an animal to learn from its environment (8-10). In this way, LHb activity, which is aversive (1, 11-13), can provide "teaching" signals to an animal: increased LHb activity (i.e., if actual reward value is less than expected) discourages repeating a behavior in the future (11,12,14), while decreased LHb activity is thought to reinforce a behavior.Human and nonhuman animal studies indicate that stressinduced changes in LHb activity may contribute to depression by suppressing reward-based behavior (1,(15)(16)(17)(18). While stress decreases reward sensitivity (19,20), is a major risk factor for depression (21, 22), forms the basis for most animal models of depression (23-25), and causes plasticity in the LHb (26-31), its effects on LHb reward and RPE signals are not known. Here, we use calcium-imaging techniques to monitor RPE from individual LHb neurons in awake, behaving mice in the absence and presence of intermittent tail shock stress. Surprisingly, we find that stress causes the LHb to respond to rewards as if they were punishment. This switch is tightly linked temporally with onset of anhedonic behavior, suggesting that this aberrant LHb responsivity contributes to anhedonia (29)(30)(31)(32)(33)(34)(35). These changes were also accompanied by a larger (i.e., "more negative") LHb signal to reward omission. Our results indicate that stress causes a negative shift in LHb signaling of reward and its omission. While potentially adaptive in some conditions (e.g., suppressing reward-seeking behavior during threat), repeated occurrence of such effects could contribute to the pathogenesis of depression. ResultsRPE Encoding in a Subpopulation of LHb Neurons. W...