Tonic activity in lateral habenula neurons promotes disengagement from reward-seeking behavior

Abstract

SUMMARYSurvival requires both the ability to persistently pursue goals and the ability to determine when it is time to stop, an adaptive balance of perseverance and disengagement. Neural activity in the lateral habenula (LHb) has been linked to aversion and negative valence, but its role in regulating the balance between reward-seeking and disengaged behavioral states remains unclear. Here, we show that LHb neural activity is tonically elevated during minutes-long disengagements from reward-seeking behavior, whether due to repeated reward omission or following sufficient consumption of reward. Further, we show that LHb inhibition extends ongoing reward-seeking behavioral states but does not prompt re-engagement. We find no evidence for similar tonic activity fluctuations in ventral tegmental area (VTA) dopamine neurons. Our findings implicate the LHb as a key mediator of disengagement from reward-seeking behavior in multiple contexts and argue against the idea that the LHb contributes to decisions solely by signaling aversion.

Response Flexibility: The Role of the Lateral Habenula

“…The mPFC-LHb-raphe projection was implicated in freezing behavior in response to a stressor. Interestingly, these findings are consistent with the theory that the mPFC relays context-specific information to the LHb, which can serve as a brake signal (Sleezer et al, 2021 ) to cease behaviors when appropriate or to engage behaviors in other aversive contexts.…”

“…For example, encountering an unexpected reward should result in phasic LHb cell firing, which would signal efferent structures to increase HPC theta to resolve a potential conflict between expected and actual context features (Mizumori et al, 1999 ). When tracking sensory/behavioral information across this relatively short period, the LHb may be serving as a brake signal to halt the initiation of potential inappropriate behaviors thereby allowing other adaptive behaviors to commence (Sleezer et al, 2021 ). When faced with other aversive situations, LHb output may instead result in the engagement of avoidance behaviors.…”

Infralimbic parvalbumin neural activity facilitates cued threat avoidance

“…In prefrontal cortex, PV neurons are critical for task performance, particularly during performance of tasks that require flexible behavior, such as rule shift learning (Cho et al, 2020) and reward extinction (Sparta et al, 2014). These studies and our findings support the idea that PV neural activity supports the execution of a behavior by filtering conflicting behaviors, each likely mediated by a different subcortical-projecting pyramidal population (Lee et al, 2014;Sleezer et al, 2021;Warden et al, 2012). In proactive defense, vmPFC PV neurons likely suppress pro-freezing vmPFC projection neurons, to enable the freezing-suppressing vmPFC-ITC projection (Berretta et al, 2005;Vertes, 2006Vertes, , 2004) and vmPFC-BMA projection (Adhikari et al, 2015) to gain control of behavior through mutual inhibition among PV neurons (Berretta et al, 2005;Gibson et al, 1999;Lee et al, 2014;Pfeffer et al, 2013).…”

A neural substrate of sex-dependent modulation of motivation

“…This previous work identified a distributed network of brain regions that contribute to value-based decisions, including the anterior cingulate cortex (ACC) as well as its major striatal target (the dorsomedial striatum, or DMS) [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] . These regions may be important not only for the value-dependent selection of actions, but also in regulating motivation to engage in reward-seeking behavior, which is also modulated by value (or expected reward) of the environment or chosen action 29,[36][37][38][39][40][41][42][43][44] . However, it remains unknown if and how differences in neural activity in these regions are responsible for producing behavioral differences between the sexes.…”