Biology subjects

Ottenheimer, D. J.

Publications and source records attributed to Ottenheimer, D. J..

8 recordsLinked to original sources

bioRxiv2026

The Central Nucleus of the Amygdala Encodes the Motivation to Pursue Ethanol

Prior studies implicate the central nucleus of the amygdala (CeA) in reward motivation, yet how this region encodes motivation for ethanol (EtOH) seeking and consumption-and how this compares to encoding of natural rewards--remains poorly understood. We recorded single-unit neural activity from rats during a cued instrumental task in which lever insertion on each trial indicates the opportunity to lever press for ethanol and post-press lever retraction signals ethanol delivery. We found neurons responsive to multiple trial events (lever insertion and retraction cues, lever press, port entry, and reward licks), including neurons with rhythmic activity entrained to licking during EtOH consumption. Notably, CeA neural responses to the lever insertion cue at trial start encoded both the likelihood and speed of engagement during reward seeking. Using a supervised classifier, we found that trial engagement and motivation level could be decoded from pre-trial and lever insertion response periods. Finally, we assessed whether these effects generalized to natural reward seeking. Sucrose-rewarded rats (both ethanol-exposed and ethanol-naive) showed higher motivation (more rewards earned and shorter first-press latencies) and stronger CeA recruitment and responses at lever insertion than ethanol-rewarded rats, in agreement with the notion that CeA circuits amplify reward-predictive cue signals to facilitate rapid action initiation under high motivational states. Together, these findings indicate that CeA neurons dynamically encode motivational states, with tonic activity and reward-predictive cue responses predicting both engagement in reward seeking and the vigor of action initiation. We suggest these patterns of neural activity drive ethanol and sucrose pursuit. Significance StatementHow motivational states drive reward-seeking is a central question in systems neuroscience, yet the mechanisms linking neural signals to action initiation remain poorly understood. Recording single-unit activity in the amygdala central nucleus (CeA) during cued ethanol self-administration revealed that neural responses to reward-predictive cues encoded both the decision to engage in reward seeking and the vigor of action initiation, and motivational state was decoded from cue-evoked signals and tonic activity even before cue presentation. Consistent with greater motivation for the more palatable sucrose reward, CeA neurons showed stronger cue responses and greater anticipatory firing preceding tongue contact with reward, compared with ethanol-rewarded rats. These findings identify CeA activity patterns that link motivational state to the rapid initiation of goal-directed action.

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bioRxiv2024

Single-cell sequencing of rodent ventral pallidum reveals diverse neuronal subtypes with non-canonical interregional continuity

The ventral pallidum (VP) was defined as a basal ganglia nucleus with dense input from ventral striatum. To further investigate a VP regional identity, we conducted a cross-species transcriptional characterization of VP cell types. We performed single nucleus RNA-sequencing of VP tissue from mice and rats and identified 16 VP neuronal subclasses with striking cross-species conservation. VP GABAergic neurons were surprisingly heterogeneous, consisting of 14 sub-classes from 3 developmental classes. Combining our sequencing data with a spatial atlas revealed that all VP subclasses extended beyond the traditional borders of VP. Integrating our VP data with prior sequencing data from striatal, hypothalamic, and extended amygdalar tissue confirmed that cell types are shared among these regions. Due to the role of VP in feeding behavior, we also assessed the transcriptional impact of high-fat diet consumption, which induced altered expression of genes involved in oxidative phosphorylation and inhibitory signaling. Overall, our results demonstrate that VP is not a transcriptionally discrete nucleus; rather, VP contains cell types with diverse expression patterns that overlap with regions beyond the basal ganglia.

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bioRxiv2024

Basolateral amygdala population coding of a cued reward seeking state depends on orbitofrontal cortex

Basolateral amygdala (BLA) neuronal responses to conditioned stimuli are closely linked to the expression of conditioned behavior. An area of increasing interest is how the dynamics of BLA neurons relate to evolving behavior. Here, we recorded the activity of individual BLA neurons across the acquisition and extinction of conditioned reward seeking and employed population-level analyses to assess ongoing neural dynamics. We found that, with training, sustained cue-evoked activity emerged that discriminated between the CS+ and CS-and correlated with conditioned responding. This sustained population activity continued until reward receipt and rapidly extinguished along with conditioned behavior during extinction. To assess the contribution of orbitofrontal cortex (OFC), a major reciprocal partner to BLA, to this component of BLA neural activity, we inactivated OFC while recording in BLA and found blunted sustained cue-evoked activity in BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in BLA also reduced reward seeking. Our data suggest that sustained cue-driven activity in BLA, which in part depends on OFC input, underlies conditioned reward-seek-ing states.

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bioRxiv2023

Contexts facilitate dynamic value encoding in the mesolimbic dopamine system

Adaptive behavior in a dynamic environment often requires rapid revaluation of stimuli that deviates from well-learned associations. The divergence between stable value-encoding and appropriate behavioral output remains a critical test to theories of dopamines function in learning, motivation, and motor control. Yet how dopamine neurons are involved in the revaluation of cues when the world changes to alter our behavior remains unclear. Here we make use of pharmacology, in vivo electrophysiology, fiber photometry, and optogenetics to resolve the contributions of the mesolimbic dopamine system to the dynamic reorganization of reward-seeking. Male and female rats were trained to discriminate when a conditioned stimulus would be followed by sucrose reward by exploiting the prior, non-overlapping presentation of a separate discrete cue - an occasion setter. Only when the occasion setters presentation preceded the conditioned stimulus did the conditioned stimulus predict sucrose delivery. As a result, in this task we were able to dissociate the average value of the conditioned stimulus from its immediate expected value on a trial-to-trial basis. Both the activity of ventral tegmental area dopamine neurons and dopamine signaling in the nucleus accumbens were essential for rats to successfully update behavioral responding in response to the occasion setter. Moreover, dopamine release in the nucleus accumbens following the conditioned stimulus only occurred when the occasion setter indicated it would predict reward. Downstream of dopamine release, we found that single neurons in the nucleus accumbens dynamically tracked the value of the conditioned stimulus. Together these results reveal a novel mechanism within the mesolimbic dopamine system for the rapid revaluation of motivation.

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bioRxiv2023

Encoding and context-dependent control of reward consumption within the central nucleus of the amygdala

The ability to evaluate and select a preferred option among a variety of available offers is an essential aspect of goal-directed behavior. Dysregulation of this valuation process is characteristic of alcohol use disorder, with the central amygdala being implicated in persistent alcohol pursuit. However, the mechanism by which the central amygdala encodes and promotes the motivation to seek and consume alcohol remains unclear. We recorded single-unit activity in male Long-Evans rats as they consumed 10% ethanol or 14.2% sucrose. We observed significant activity at the time of approach to alcohol or sucrose, as well as lick-entrained activity during the ongoing consumption of both alcohol and sucrose. We then evaluated the ability of central amygdala optogenetic manipulation time-locked to consumption to alter ongoing intake of alcohol or sucrose, a preferred non-drug reward. In closed two-choice scenarios where rats could drink only sucrose, alcohol, or quinine-adulterated alcohol with or without central amygdala stimulation, rats drank more of stimulation-paired options. Microstructural analysis of licking patterns suggests these effects were mediated by changes in motivation, not palatability. Given a choice among different options, central amygdala stimulation enhanced consumption if the stimulation was associated with the preferred reward while closed-loop inhibition only decreased consumption if the options were equally valued. However, optogenetic stimulation during consumption of the less-preferred option, alcohol, was unable to enhance overall alcohol intake while sucrose was available. Collectively, these findings indicate that the central amygdala processes the motivational value of available offers to promote pursuit of the most preferred available option.

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bioRxiv2022

A stable, distributed code for cue value in mouse cortex during reward learning

The ability to associate reward-predicting stimuli with adaptive behavior is frequently attributed to the prefrontal cortex, but the stimulus-specificity, spatial distribution, and stability of pre-frontal cue-reward associations are unresolved. We trained headfixed mice on an olfactory Pavlovian conditioning task and measured the coding properties of individual neurons across space (prefrontal, olfactory, and motor cortices) and time (multiple days). Neurons encoding cues or licks were most common in olfactory and motor cortex, respectively. By quantifying the responses of cue-encoding neurons to six cues with varying probabilities of reward, we unexpectedly found value coding in all regions we sampled, with some enrichment in prefrontal cortex. We further found that prefrontal cue and lick codes were preserved across days. Our results demonstrate that individual prefrontal neurons stably encode components of cue-reward learning within a larger spatial gradient of coding properties.

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bioRxiv2021

Dorsomedial striatal activity tracks completion of behavioral sequences

For proper execution of goal-directed behaviors, individuals require both a general representation of the goal and an ability to monitor their own progress toward that goal. Here, we examine how dorsomedial striatum (DMS), a region pivotal for forming associations among stimuli, actions, and outcomes, encodes the execution of goal-directed action sequences that require self-monitoring of behavior. We trained rats to complete a sequence of at least 5 consecutive lever presses (without visiting the reward port) to obtain a reward and recorded the activity of individual cells in DMS while rats performed the task. We found that the pattern of DMS activity gradually changed during the execution of the sequence, permitting accurate decoding of sequence progress from neural activity at a population level. Moreover, this sequence-related activity was blunted on trials where rats did not complete a sufficient number of presses. Overall, these data suggest a link between DMS activity and the execution of behavioral sequences that require monitoring of ongoing behavior.

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bioRxiv2019

A history-derived reward prediction error signal in ventral pallidum

Learning from past interactions with the environment is critical for adaptive behavior. Within the framework of reinforcement learning, the nervous system builds expectations about future reward by computing reward prediction errors (RPEs), the difference between actual and predicted rewards. Correlates of RPEs have been observed in the midbrain dopamine system, which is thought to locally compute this important variable in service of learning. However, the extent to which RPE signals may be computed upstream of the dopamine system is largely unknown. Here, we quantify history-based RPE signals in the ventral pallidum (VP), an input region to the midbrain dopamine system implicated in reward-seeking behavior. We trained rats to associate cues with future delivery of reward and fit computational models to predict individual neuron firing rates at the time of reward delivery. We found that a subset of VP neurons encoded RPEs and did so more robustly than nucleus accumbens, an input to VP. VP RPEs predicted trial-by-trial task engagement, and optogenetic inhibition of VP reduced subsequent task-related reward seeking. Consistent with reinforcement learning, activity of VP RPE cells adapted when rewards were delivered in blocks. We further found that history- and cue-based RPEs were largely separate across the VP neural population. The presence of behaviorally-instructive RPE signals in the VP suggests a pivotal role for this region in value-based computations.

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