Biology subjects

Burdakov, D.

Publications and source records attributed to Burdakov, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Rules of disengagement: orexin-arousal and dopamine-utility as separable axes

Staying on task, leaving it, and coming back to it are processes we experience daily. They depend on task utility and arousal, but the neurochemical processes behind this interplay are unknown. In mice performing a decision-making task with shifting reward size, we identified latent engagement states and the transitions between them. Pupil-linked arousal and dopaminergic utility coding predicted these transitions along separable axes. Orexin antagonism with almorexant disengaged mice at low reward, an effect mediated by pupil-linked arousal and not by dopamine. GLP-1 receptor agonism with semaglutide reduced the gain with which accumbal dopamine integrates reward history, which predicted the progressive disengagement it caused, with no detectable contribution from arousal or orexin. Fast striatal and slow accumbal dopamine codes predicted engagement on their own timescales. These results decouple orexin-driven arousal from dopamine-mediated utility coding in task engagement, with implications for two widely used drug classes and for disorders of motivation.

neuroscience↗

bioRxiv2026

Dissociable control of persistence and adaptive updating in reward-guided behavior

Adaptive behavior requires a balance between persistence and flexibility, whereas excessive persistence and impaired updating characterize several neuropsychiatric disorders. Touchscreen-based cognitive tasks provide a reverse-translational framework because closely related visual-discrimination and reversal paradigms are used to phenotype cognitive flexibility in rodents and humans. Here, we examined the role of the melanin-concentrating hormone (MCH) system using appetitive touchscreen extinction and reversal tasks. Blocking MCHR1 had little effect while an established reward contingency remained valid, but facilitated behavioral adaptation when reinforcement was withdrawn or reversed. These findings suggest that MCHR1 signaling promotes persistence of previously reinforced behavior. We then chemogenetically activated lateral hypothalamic MCH neurons. Activation produced no detectable change in extinction, but altered learning during reversal. Notably, behavioral differences were also evident during a subsequent reversal performed without chemogenetic activation: mice previously exposed to MCH-neuron activation learned the new contingency more rapidly, yet showed greater persistence after individual errors. Thus, MCHR1 blockade and MCH-neuron activation affect distinct components of behavioral updating rather than producing simple opposite effects. Together, these findings identify dissociable MCH-system contributions to reward-contingency updating in a behavioral framework directly relevant to cross-species neuropsychiatric research.

animal behavior and cognition↗

bioRxiv2026

Melanin-concentrating hormone signaling regulates persistence and updating of reward-guided actions

Flexible behavior requires persistence when a strategy remains effective and rapid updating when its consequences change. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus regulate feeding, reward and memory, but their contribution to reward guided flexibility is unknown. Here, mice learned an action-outcome contingency in a T-maze and then adapted when the reward location switched. MCHR1 antagonism throughout learning did not measurably alter Initial Learning but reduced perseverative choices and accelerated behavioral adaptation after the contingency switched. Endogenous LH-MCH activity was strongest while contingencies were being established or revised, declined as performance stabilized, distinguished rewarded from unrewarded outcomes, and reflected current outcomes in the context of recent and accumulated experience. MCHR1 blockade altered prelimbic responses to successful outcomes in both phases and opposed their progressive weakening during Rule Switch. Together, these findings identify MCH signaling as a regulator of how strongly past reward continues to guide behavior when contingencies change and reveal accompanying changes in prefrontal processing of successful outcomes.

neuroscience↗

bioRxiv2026

Melanin-concentrating hormone signaling regulates prefrontal updating of learned avoidance

Adaptive avoidance depends on a delicate balance: animals must act rapidly when a cue predicts danger, but suppress the same action when the cue no longer has consequence. How MCH neuromodulatory signaling shapes this prefrontal updating process remains poorly understood. Here, we identify melanin-concentrating hormone receptor 1 (MCHR1) signaling as a regulator of active avoidance extinction. Pharmacological MCHR1 antagonism with SNAP-94847 left acquisition of two-way active avoidance intact, but promoted extinction once the tone was no longer followed by shock. This effect was reproduced by prelimbic mPFC-targeted SNAP infusion, indicating that prefrontal MCHR1 signaling contributes to the persistence of learned avoidance. Fiber photometry from CaMKII-positive mPFC neurons revealed that MCHR1 antagonism enhanced excitatory prefrontal activity during successful avoidance and altered trial-history-dependent mPFC activity during extinction, most prominently on avoidance trials that followed previous avoidance. These findings identify MCHR1 signaling as a regulator of adaptive avoidance updating and suggest that MCHR1 antagonism facilitates extinction by altering prefrontal processing of recent action history when a formerly protective response loses behavioral value. Significance StatementIn anxiety- and trauma-related disorders, avoidance can persist long after danger is gone, interfering with daily life. While avoidance is essential for survival, it can become harmful when it is no longer needed. We found that blocking brain receptors for melanin-concentrating hormone helps mice stop responding to outdated warning signals while preserving their ability to learn from danger. We identify the medial prefrontal cortex as a key brain region where this intervention changes activity during fear-guided behavior. This study highlights a potential therapeutic strategy for reducing excessive avoidance without compromising normal protective responses.

neuroscience↗

bioRxiv2025

A rapid arousal brake on hunger neurons and its release in narcolepsy

The brain must constantly integrate internal needs with external cues, requiring it to evaluate potential rewards and prioritize urgent environmental demands. How arousal systems control hunger to achieve this is a fundamental question. We targeted the functional connection from arousal hypocretin/orexin neurons (HONs) to hunger (AGRP) neurons and discovered that it operates through a local GABAergic relay, revealing a circuit for rapid, arousal-driven hunger suppression. We found this suppression deployed in several critical functions. In appetitive evaluation, it controls food value perception by suppressing AGRP based on a foods predicted caloric worth. In adaptive vigilance, it creates an opportunity to prioritize other needs, such as responding to novel, arousing stimuli. During spontaneous pupil dilations, it creates hunger-free windows for optimal assessment of the environment. These findings reveal a fundamental inhibitory circuit that allows pupil-linked arousal to dynamically gate hunger on a moment-to-moment basis, providing a new framework for how the brain balances competing internal and external demands.

neuroscience↗

bioRxiv2025

Neurometabolic signaling and control of policy complexity

Cognition and adaptive behavior emerge from neural information processing. This must operate within finite metabolic constraints, since neural information processing is metabolically expensive. While neural implementations of action selection and learning are well-studied, systems allocating the informational capacity required to encode complex behavioral policies remain unknown. We hypothesized that hypothalamic hypocretin/orexin neurons (HONs) are uniquely positioned to signal and control policy complexity, given that they are activated by metabolic depletion and influence decision-making systems. To explore this, we employed a set of cell/neurotransmitter-specific imaging and causal manipulations during a multi-armed bandit task where freely behaving mice learned probabilistic state-action-reward relationships (together [~]100,000 decisions from >100 mice). Miniscope recordings of HON activity revealed that pre-choice, but not post-choice activity correlates with decision policy, dissociating decisions from feedback. Furthermore, manipulating HON signals with optogenetics and pharmacology confirmed that they causally regulate the development of complex policies. Finally, neurotransmitter-specific sensors revealed that hypocretin/orexin receptors modulate decision policy-related dopamine and noradrenaline dynamics in the nucleus accumbens and medial prefrontal cortex. These findings identify HONs as subcortical regulators of policy complexity, encoding critical signals for decision-making adjustments. This opens a new window for the development of comprehensive mechanistic models of strategic learning which account for interplay between decision-making policies and metabolic/informational constraints, and may guide the development of potential treatments for disorders with policy deficits such as autism and schizophrenia.

neuroscience↗

bioRxiv2024

Distinct bandwidths of orexin neuron activity independently encode body movement and metabolic state

Tracking net body movement in real time may enable the brain to estimate ongoing demands and thus better orchestrate muscle tone, energy balance, and arousal. To identify neural populations specializing in tracking net body movement, here we compared self-initiated movement-related activity across genetically-defined subcortical neurons in the mouse brain, including dopaminergic, glutamatergic, noradrenergic, and key peptidergic neurons. We show that hypothalamic orexin/hypocretin-producing neurons (HONs) are exceptionally precise movement-trackers, encoding net body movement across multiple classified behaviors with a high degree of precision, independent of head acceleration. This tracking was so precise, that video analysis of the mouse body movement reliably served as a low-cost biometric for HON population activity. The movement tracking was independent of internal nutritional states, and occurred in a communication bandwidth distinct from HON encoding of blood glucose. At key projection targets, orexin/hypocretin peptide outputs correlated with self-initiated movement in a projection-specific manner, indicating functional heterogeneity in HON outputs. Finally, we found that body movement was not encoded to the same extent in other key neural populations related to arousal or energy. These findings indicate that subcortical orchestrators of arousal and metabolism are finely tuned to encode net body movement, constituting a bridge multiplexing ongoing motor activity with internal energy resources.

neuroscience↗

bioRxiv2023

A neuropsychological basis for temptation-resistant voluntary exercise

Despite well-known health benefits of physical activity, many people under-exercise, and what drives prioritization of exercise over other alternatives is unclear. We implement a novel paradigm allowing to study how freely behaving mice rapidly display such prioritizing between time spent on wheel-running and other temptations such as palatable food. Causal manipulations and correlative analyses of underlying appetitive and consummatory psychobehavioral processes revealed this prioritizing to be instantiated by hypothalamic hypocretin/orexin neurons.

neuroscience↗

bioRxiv2023

Exploratory rearing is governed by hypothalamic MCH cells according to the locus coeruleus

Exploration is essential for survival because it allows animals to gather information about their environment. Rearing is a classic exploratory behavior, during which an animal transiently stands on its hind legs to sample its environment. It is widely observed in common lab conditions as well as in the wild, yet neural signals and circuits underlying this fundamental component of innate behavior remain unclear. We examined behavioral correlates of activity in hypothalamic MCH-producing neurons (MNs) - a recently characterized but still poorly understood neural type - and found that MN activation co-occurs with exploratory rears in mice. Complementary optogenetic and pharmacological manipulations indicated that MN activity selectively promotes rearing via G-protein coupled MCHR1 receptors. Furthermore, we show in vivo that activation of the locus coeruleus noradrenergic neurons rapidly inhibits MNs and suppresses rearing through MCHR1-dependent pathways. Overall, these findings define a subcortical neural module which both tracks and controls exploratory rearing.

neuroscience↗

bioRxiv2023

Stimulation of VTA dopamine inputs to LH upregulates orexin neuronal activity in a DRD2-dependent manner

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the LH. We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons, and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is partially dependent on dopamine D2 receptors (DRD2). Our results reveal previously unknown orexinergic coding of reward expectation and unveil an orexin-regulatory axis mediated by local dopamine inputs in the LH. HighlightsO_LIOptical VTA DA neuron stimulation is sufficient to elicit a Pavlovian-like dopamine transient in the NAc C_LIO_LIDopamine in the LH encodes both negative and positive reward prediction errors C_LIO_LIDopamine in the LH positively modulates orexin neuronal activity locally in a D2R dependent way C_LI

neuroscience↗

bioRxiv2023

Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a new feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.

neuroscience↗

bioRxiv2022

A role for MCH neuron firing in hippocampal plasticity and learning

It has been revealed that melanin-concentrating hormone (MCH) neurons in the hypothalamus can influence learning (Liu et al., 2022) and memory formation (Kosse & Burdakov, 2019), but the cellular mechanisms by which they perform this function are not understood. Here, we examine the role of MCH neural input to the hippocampus, and show in vitro that optogenetically increasing MCH axon activity facilitates hippocampal plasticity by lowering the threshold for synaptic potentiation. In vivo, we find that MCH neurons are naturally active in response to reinforcing cues during a spatial learning task, and that this activity is correlated with the speed of learning. Together, our results align with increasing evidence that MCH neurons play an on-line regulatory role in learning, and reveal that this could be achieved through modulation of synaptic plasticity in the hippocampus.

neuroscience↗

bioRxiv2022

Disentangling the role of NAc D1 and D2 cells in hedonic eating

Overeating is driven by both the hedonic component ( liking) of food, and the motivation ( wanting) to eat it. The nucleus accumbens (NAc) is a key brain center implicated in these processes, but how distinct NAc cell populations encode liking and wanting to shape overconsumption remains unclear. Here, we probed the roles of NAc D1 and D2 cells in these processes using cell-specific recording and control in diverse behavioral paradigms that disentangle reward traits of liking and wanting related to food choice and overeating. NAc D2 cells encoded experience-dependent development of liking, while NAc D1 cells encoded innate liking during the first food taste. Optogenetic control confirmed causal links of D1 and D2 cells to these aspects of liking. In relation to wanting, D1 and D2 cells encoded and promoted distinct aspects of food approach: D1 cells interpreted food cues while D2 cells also sustained food-visit-length that facilitates consumption. Finally, at the level of food choice, D1, but not D2, cell activity was sufficient to switch food preference, programming subsequent long-lasting overconsumption. By revealing complementary roles of D1 and D2 cells in consumption, these findings assign neural bases to liking and wanting in a unifying framework of D1 and D2 cell activity.

neuroscience↗

bioRxiv2022

Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes

The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes. Specifically, our results reveal that MCH neuron Ca+2 activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally-relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.

neuroscience↗

bioRxiv2022

Arousal neurons that anticipate deviations in blood glucose.

Blood glucose variability shapes human brain performance and diverse clinical outcomes. However, it remains poorly understood how blood glucose fluctuations are decoded by genetically-defined neurons to change brain activity and behavior. Recent breakthroughs in genetics and clinical diagnostics identified hypothalamic hypocretin/orexin neurons (HONs) as core determinants of brain activity and adaptive behavior across mammals. Here we show that low-frequency HON population waves are tuned for transmitting information about minute-to-minute temporal features of blood glucose, thus rapidly converting its variability into brain state of behaving mice. Contrary to current theories envisioning glucose-proportional neural responses, the HONs response tracked blood glucose gradients, thus generating efficient neural adaptations in anticipation of maximal glucose deviations. Resolving this population response at the single cell level with volumetric multiphoton imaging furthermore revealed glucose-excited and glucose-inhibited HONs, distinctly coupled to body movements in the high-frequency domain. Finally, HON-selective opotogenetics and cell ablation demonstrated that HONs are critical for linking glucose to adaptive behavior. These results provide an insight into how behaviorally influential hypothalamic networks interpret blood glucose variability. This may inform future metrics for efficient prediction of glycemic states in health and disease.

neuroscience↗

bioRxiv2022

Coding of reward uncertainty and probability by orexin neurons

Activation of hypothalamic hypocretin/orexin neurons (HONs) is a neural substrate of arousal. HONs activate during sensory stimuli, and are thus thought to regulate arousal according to sensory input. Here, we measured body movements occurring during sound cues or associated reward outcomes, and used an encoding model to ask whether HONs indeed specialize in tracking certain features, or multiplex diverse types of features. Although some single HONs multiplexed feature combinations, during the cue period the overall HON signal primarily tracked body movements. This persisted across cues signaling different reward probabilities, and substantially diverged from reward-probability tracking in concurrently-recorded VTA dopamine neurons. In contrast, during reward outcome, HONs predominantly signaled the presence or absence of reward, and not body movements, nor surprise or reward prediction error. These results describe an unexpectedly specialized and flexible logic of HON activation, suggesting a role for HONs in tracking actions and subsequent reinforcements.

neuroscience↗

bioRxiv2022

Control and coding of pupil size by hypothalamic orexin neurons

Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking, but their roles in rapid arousal dynamics and reward perception remain unclear. Here, cellspecific stimulation, deletion, and in vivo recordings revealed strong correlative and causal links between pupil dilation - a quantitative arousal marker - and orexin cell activity. Coding of arousal and reward was distributed across orexin cells, indicating that they specialize in rapid, multiplexed communication of momentary arousal and reward states.

neuroscience↗

bioRxiv2021

Rational inattention in mice

Behavior exhibited by humans and other organisms is generally inconsistent and biased, and thus is often labeled irrational. However, the origins of this seemingly suboptimal behavior remain elusive. We developed a behavioral task and normative framework to reveal how organisms should allocate their limited processing resources such that there is an advantage to being imprecise and biased for a given metabolic investment that guarantees maximal utility. We found that mice act as rational-inattentive agents by adaptively allocating their sensory resources in a way that maximizes reward consumption in novel stimulus-reward association environments. Surprisingly, perception to commonly occurring stimuli was relatively imprecise, however this apparent statistical fallacy implies "awareness" and efficient adaptation to their neurocognitive limitations. Interestingly, distributional reinforcement learning mechanisms efficiently regulate sensory precision via top-down normalization. These findings establish a neurobehavioral foundation for how organisms efficiently perceive and adapt to environmental states of the world within the constraints imposed by neurobiology.

neuroscience↗