Denis Burdakov

Last Name

Burdakov

First Name

Denis

ORCID

0000-0002-9134-9165

Organisational unit

09589 - Burdakov, Denis / Burdakov, Denis

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Publications1 - 10 of 24

A role for MCH neuron firing in modulating hippocampal plasticity threshold
Harris, Julia J.; Burdakov, Denis (2024)
Peptides
It has been revealed that hypothalamic neurons containing the peptide, melanin-concentrating hormone (MCH) can influence learning [1] and memory formation [2], but the cellular mechanisms by which they perform this function are not well 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. These results align with increasing evidence that MCH neurons play a regulatory role in learning, and reveal that this could be achieved by modulating plasticity thresholds in the hippocampus.
Hypothalamic deep brain stimulation as a strategy to manage anxiety disorders
Li, Han-Tao; Donegan, Dane C.; Peleg-Raibstein, Daria; et al. (2022)
Proceedings of the National Academy of Sciences of the United States of America
Fear is essential for survival, but excessive anxiety behavior is debilitating. Anxiety disorders affecting millions of people are a global health problem, where new therapies and targets are much needed. Deep brain stimulation (DBS) is established as a therapy in several neurological disorders, but is underexplored in anxiety disorders. The lateral hypothalamus (LH) has been recently revealed as an origin of anxiogenic brain signals, suggesting a target for anxiety treatment. Here, we develop and validate a DBS strategy for modulating anxiety-like symptoms by targeting the LH. We identify a DBS waveform that rapidly inhibits anxiety-implicated LH neural activity and suppresses innate and learned anxiety behaviors in a variety of mouse models. Importantly, we show that the LH DBS displays high temporal and behavioral selectivity: Its affective impact is fast and reversible, with no evidence of side effects such as impaired movement, memory loss, or epileptic seizures. These data suggest that acute hypothalamic DBS could be a useful strategy for managing treatment-resistant anxiety disorders.
Exploratory Rearing Is Governed by Hypothalamic Melanin-Concentrating Hormone Neurons According to Locus Ceruleus
Concetti, Cristina; Viskaitis, Paulius; Grujic, Nikola; et al. (2024)
The Journal of Neuroscience
Information seeking, such as standing on tiptoes to look around in humans, is observed across animals and helps survival. Its rodent analog - unsupported rearing on hind legs - was a classic model in deciphering neural signals of cognition and is of intense renewed interest in preclinical modeling of neuropsychiatric states. Neural signals and circuits controlling this dedicated decision to seek information remain largely unknown. While studying subsecond timing of spontaneous behavioral acts and activity of melaninconcentrating hormone (MCH) neurons (MNs) in behaving male and female mice, we observed large MN activity spikes that aligned to unsupported rears. Complementary causal, loss and gain of function, analyses revealed specific control of rear frequency and duration by MNs and MCHR1 receptors. Activity in a key stress center of the brain - the locus ceruleus noradrenaline cells - rapidly inhibited MNs and required functional MCH receptors for its endogenous modulation of rearing. By defining a neural module that both tracks and controls rearing, these findings may facilitate further insights into biology of information seeking.
Control and coding of pupil size by hypothalamic orexin neurons
Grujic, Nikola; Tesmer, Alexander; Bracey, Ed; et al. (2023)
Nature Neuroscience
Brain orexin (hypocretin) neurons are implicated in sleep–wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear. Here, cell-specifc 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.
Rationality, preferences, and emotions with biological constraints: it all starts from our senses
Polania, Rafael Hernan; Burdakov, Denis; Hare, Todd A. (2024)
Trends in Cognitive Sciences
Is the role of our sensory systems to represent the physical world as accurately as possible? If so, are our preferences and emotions, often deemed irrational, decoupled from these 'ground-truth' sensory experiences? We show why the answer to both questions is 'no'. Brain function is metabolically costly, and the brain loses some fraction of the information that it encodes and transmits. Therefore, if brains maximize objective functions that increase the fitness of their species, they should adapt to the objective-maximizing rules of the environment at the earliest stages of sensory processing. Consequently, observed 'irrationalities', preferences, and emotions stem from the necessity for our early sensory systems to adapt and process information while considering the metabolic costs and internal states of the organism.
Eat, seek, rest? An orexin/hypocretin perspective
Peleg-Raibstein, Daria; Viskaitis, Paulius; Burdakov, Denis (2023)
Journal of Neuroendocrinology
Seeking and ingesting nutrients is an essential cycle of life in all species. In classical neuropsychology these two behaviours are viewed as fundamentally distinct from each other, and known as appetitive and consummatory, respectively. Appetitive behaviour is highly flexible and diverse, but typically involves increased locomotion and spatial exploration. Consummatory behaviour, in contrast, typically requires reduced locomotion. Another long-standing concept is "rest and digest", a hypolocomotive response to calorie intake, thought to facilitate digestion and storage of energy after eating. Here, we note that the classical seek -> ingest -> rest behavioural sequence is not evolutionarily advantageous for all ingested nutrients. Our limited stomach capacity should be invested wisely, rather than spent on the first available nutrient. This is because nutrients are not simply calories: some nutrients are more essential for survival than others. Thus, a key choice that needs to be made soon after ingestion: to eat more and rest, or to terminate eating and search for better food. We offer a perspective on recent work suggesting how nutrient-specific neural responses shape this choice. Specifically, the hypothalamic hypocretin/orexin neurons (HONs) - cells that promote hyperlocomotive explorative behaviours - are rapidly and differentially modulated by different ingested macronutrients. Dietary non-essential (but not essential) amino acids activate HONs, while glucose depresses HONs. This nutrient-specific HON modulation engages distinct reflex arcs, seek -> ingest -> seek and seek -> ingest -> rest, respectively. We propose that these nutri-neural reflexes evolved to facilitate optimal nutrition despite the limitations of our body.
Orexin neurons track temporal features of blood glucose in behaving mice
Viskaitis, Paulius; Tesmer, Alexander L.; Liu, Ziyu; et al. (2024)
Nature Neuroscience
Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to this new state. Hypothalamic arousal-orchestrating hypocretin/orexin neurons (HONs) have been proposed to be glucose sensors, yet whether they track glucose concentration (proportional tracking) or rate of change (derivative tracking) is unknown. Using simultaneous recordings of HONs and blood glucose in behaving male mice, we found that maximal HON responses occur in considerable temporal anticipation (minutes) of glucose peaks due to derivative tracking. Analysis of >900 individual HONs revealed glucose tracking in most HONs (98%), with derivative and proportional trackers working in parallel, and many (65%) HONs multiplexed glucose and locomotion information. Finally, we found that HON activity is important for glucose-evoked locomotor suppression. These findings reveal a temporal dimension of brain glucose sensing and link neurobiological and algorithmic views of blood glucose perception in the brain’s arousal orchestrators.
Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats
Subramanian, Keshav S.; Lauer, Logan Tierno; Hayes, Anna M. R.; et al. (2023)
Nature Communications
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 in male rats. Specifically, results reveal that MCH neuron Ca2+ 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.
Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy
Li, Han-Tao; Viskaitis, Paulius; Bracey, Eva; et al. (2024)
Nature Communications
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 male 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 feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.
Orexin neurons mediate temptation-resistant voluntary exercise
Tesmer, Alexander L.; Li, Xinyang; Bracey, Eva; et al. (2024)
Nature Neuroscience
Despite the well-known health benefits of physical activity, many people underexercise; what drives the prioritization of exercise over alternative options is unclear. We developed a task that enabled us to study how mice freely and rapidly alternate between wheel running and other voluntary activities, such as eating palatable food. When multiple alternatives were available, mice chose to spend a substantial amount of time wheel running without any extrinsic reward and maintained this behavior even when palatable food was added as an option. Causal manipulations and correlative analyses of appetitive and consummatory processes revealed this preference for wheel running to be instantiated by hypothalamic hypocretin/orexin neurons (HONs). The effect of HON manipulations on wheel running and eating was strongly context-dependent, being the largest in the scenario where both options were available. Overall, these data suggest that HON activity enables an eat–run arbitration that results in choosing exercise over food.

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Denis Burdakov

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