Biology subjects

Bracey, E.

Publications and source records attributed to Bracey, E..

4 recordsLinked to original sources

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

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

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↗