Stress transforms lateral habenula reward responses into punishment signals

Abstract

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...

Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

“…These data also suggest that there may be a disconnect between the transcriptional definition of cell types, and their functional encoding dynamics in vivo or ex vivo following aversive stimulus exposure. Electrophysiological (Amo et al, 2014;Cui et al, 2018;Lecca et al, 2017;Li et al, 2011;Yang et al, 2018) and calcium imaging (Shabel et al, 2019) studies show that large proportions of LHb neurons display an increase in their firing/activity rate in response to, or following aversive stimuli exposure, while our transcriptional profiling results suggests more molecular heterogeneity exists. Thus, it seems likely that despite the striking transcriptional differences across habenula cells, their activity dynamics could be similar (at least in response to simple aversive stimuli exposure), and driven largely by their anatomical connectivity.…”

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“…A Go/NoGo task requires the animal to refrain from responding in S− trials. Studies in different vertebrates show that neurons of the HbL code for negative events 55 and are able to downregulate the activity of dopaminergic VTA cells 56 . As a result, the HbL plays a key role in aversion-induced behavioral suppression by generating a feedback signals that discourages behavioral repetition 57 .…”

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“…Unlike the wild type (WT), cLH rats exhibit a helpless phenotype without prior exposure to stress, as demonstrated in the shuttle box or forced swim test (37). Consistent with its modeling maladaptive valence processing, cLH animals display abnormal reward responses like those observed in depressed patients (38)(39)(40). Furthermore, this line displays several depression-like symptoms (e.g., anhedonia, avolition, weight changes) (41) that improve with drugs (42)(43)(44) used to treat human depression, including ketamine (35).…”