Biology subjects

Kaye, A. P.

Publications and source records attributed to Kaye, A. P..

13 recordsLinked to original sources

bioRxiv2026

An adaptive noradrenergic-prefrontal circuit for innate avoidance of heights

Innate preferences determine how animals interact with the environment, but how experience refines the neural processes underlying those intrinsic motivations is not well understood. Here we develop a virtual pole descent task which permitted in which mice can repeat many trials without habituation of height-dependent avoidance. Mice adjusted their choices based on recent trial outcomes without externally imposed behavioral reinforcement or punishment. Using this paradigm, we found that noradrenergic signaling enhances height avoidance while experience refines the prefrontal cortex population representation of the task. Inhibiting locus coeruleus norepinephrine neurons reduced safe choices in apparently tall visual height stimuli, while stimulating their projections to prelimbic cortex enhanced safe decision-making. Anticipatory norepinephrine in prelimbic cortex correlated with height avoidance across animals and reflected trial outcome history. Miniscope calcium imaging revealed prelimbic neurons tracked progress in the task. At the population level, experience induced improvements in the decoding of position which correlated strongly with behavioral improvements. With experience, neural trajectories became less variable during the task and reliability of representations correlated with behavioral improvement. Together these results reveal that innate threat experience can induce prefrontal cortical refinement without externally imposed reinforcement. Innate behavioral preference is thus maintained while the neural processes underlying it evolve, suggesting flexibility in neural circuits for interacting with hardwired environmental motivations.

neuroscience↗

bioRxiv2026

Human claustrum neurons encode uncertainty and prediction errors during aversive learning

Flexible behavior depends on continuous updating of internal models, yet the neural circuits coordinating this process remain poorly understood [1]. The claustrum -- reciprocally connected to nearly the entire neocortex -- is uniquely positioned to influence cortical processing. Here we report single-neuron recordings from the human claustrum during aversive learning [2], with anterior cingulate cortex and amygdala recordings for comparison. Claustrum and anterior cingulate neurons displayed structured, task-related responses. Distinct subpopulations encoded stimulus onset and action-contingent outcomes, with outcome representations diverging between regions. Critically, both regions encoded model-derived latent variables -- uncertainty and prediction error -- but with different temporal profiles: only the anterior cingulate carried uncertainty signals during the intertrial period, while both regions encoded uncertainty and prediction error during the active-avoidance period. The amygdala, by contrast, showed minimal latent-variable modulation. These findings provide evidence that human claustrum neurons track higher-order cognitive variables not directly observable from sensory input, and reveal dissociable roles for the claustrum and anterior cingulate cortex in tracking latent task states.

neuroscience↗

bioRxiv2026

Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response

Psilocybin has antidepressant effects, but its 5-HT2AR-mediated perceptual effects limit tolerability. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) and observed suppression of head-twitch response, but maintenance of antidepressant-like behavior. Proteomics showed that PDE9i-psilocybin reduced 5-HT2AR-mediated pathways while enhancing synaptogenesis. These results suggest that PDE9i-psilocybin represents a promising therapeutic strategy.

neuroscience↗

bioRxiv2026

MDMA enhances prefrontal plasticity and representational drift during fear extinction

Fear extinction requires dynamic updating of cortical representations, yet the neural mechanisms underlying successful extinction remain poorly understood. Some psychoactive substances induce structural plasticity in medial prefrontal cortex (mPFC), possibly underlying their therapeutic potential. Here we investigated whether MDMA, which enhances fear extinction, induces prefrontal structural and functional plasticity, and measured its effects on ensemble representations during extinction. Longitudinal two-photon microscopy revealed that MDMA increased spine density and spinogenesis across prefrontal subregions. Miniscope Ca{superscript 2} imaging in infralimbic cortex (IL) during fear extinction revealed that IL became more correlated with the suppression of freezing behavior, consistent with a strengthening of its role in extinction. Longitudinal cell registration demonstrated accelerated representational drift across days in MDMA-treated mice; this effect was strongest in a functionally defined subpopulation of neurons that showed suppression of activity to conditioned cues. These findings demonstrate that MDMA facilitates structural and functional neuroplasticity, potentially underlying its enhancement of extinction learning.

neuroscience↗

bioRxiv2025

Beta bursts mediate amygdala gating of hippocampal emotional encoding

The amygdala and hippocampus are key structures in emotional processing, yet the transient neural dynamics coordinating their interaction remain poorly understood. We simultaneously recorded single-neuron activity and local field potentials from these regions in epilepsy patients performing an emotional image-rating task. Neurons in both areas exhibited firing rate changes predictive of subjective emotional valence. While conventional spectral analysis revealed no valence-specific patterns, beta bursts (13-30 Hz)--transient, high-power events-were uniquely modified by task features. In both regions, beta bursts were associated with increased gamma amplitude and enhanced phase coherence, with beta-gamma phase-amplitude coupling capturing emotion-related dynamics. Critically, amygdala beta bursts were associated with strong suppression of hippocampal firing, coinciding with interneuron activation, during negative valence/highest arousal processing, whereas hippocampal bursts showed no reciprocal influence. These findings suggest that beta bursts may represent a temporally precise neural correlate of emotional appraisal and a candidate mechanism for targeted neuromodulation in mood disorders.

neuroscience↗

bioRxiv2024

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors

The brainstem cell group, locus coeruleus (LC), is present across vertebrates and influences cardiorespiratory, metabolic, immune, and cognitive functions by activating in two putatively distinct firing patterns. Yet, the degree to which the LC firing rates and patterns are homogenous across species has never been assessed due to inherently limited sample sizes. To remedy this, we pooled cross-species data from 20 laboratories to show that firing rates differ across species and are modulated by sex, age, and type of in vitro or in vivo preparation. Contrary to the prevailing dual-mode firing pattern schema, we observed patterns spread across a low-dimensional manifold, with subregions enriched for specific biological factors and neurodegenerative disease models. Our findings show considerable diversity in an ancestral vertebrate neuromodulatory system.

neuroscience↗

bioRxiv2024

Classification of psychedelic drugs based on brain-wide imaging of cellular c-Fos expression

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.

neuroscience↗

bioRxiv2024

The human claustrum tracks slow waves during sleep

Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies posit that the claustrum, a small subcortical nucleus, coordinates slow waves. We recorded claustrum neurons in humans during sleep. In contrast to neurons from other brain regions, claustrum neurons increased their activity and tracked slow waves during NREM sleep suggesting that the claustrum plays a role in human sleep architecture.

neuroscience↗

bioRxiv2023

Frontal cortex norepinephrine, serotonin, and dopamine dynamics in an innate fear-reward behavioral model

Animals must survive by foraging for food in an uncertain and dangerous world. Neural circuits for naturalistic decision-making under these conditions must balance competing motivational demands for approaching reward and avoiding danger. To enable flexible switching between motivational states, neuromodulators are released and alter neural excitability and plasticity. The question of how neuromodulators encode motivational state is thus fundamental to systems neuroscience, yet the dynamics of neuromodulators during naturalistic decision making are not fully understood. Here, we developed a naturalistic approach/avoidance task in mice involving a tradeoff between seeking reward versus safety in the presence of looming predation risk. We utilized fiber photometry, computational behavior tracking, and local pharmacology in this task. Silencing medial prefrontal cortex (mPFC) reduced looming defensive behaviors. Moreover, by using fiber photometry combined with GPCR-based sensors, we found that cortical norepinephrine (NE) plays a more prominent role in encoding looming threats while dopamine (DA) represents reward and threat. In contrast, serotonin (5HT) dynamic negatively correlates to both emotional valences. To begin to understand neuromodulatory interactions, we used ex vivo slice physiology to understand 5HT impact on spontaneous firing of locus coeruleus NE neurons. In conclusion, monoamines such as NE, DA, 5HT can converge in their encoding of naturalistic motivated behaviors as well as dissociate from one another. By utilizing this novel innate reward-threat task, we can better understand neurochemical signaling events during natural behavior, and may contribute to the understanding of neural mechanisms underlying emotional decision-making and its implications for psychiatric disorders.

neuroscience↗

bioRxiv2023

Spatiotemporal organization of prefrontal norepinephrine influences neuronal activity

Norepinephrine (NE), a neuromodulator released by locus coeruleus neurons throughout cortex, influences arousal and learning through extra-synaptic vesicle exocytosis. While NE within cortical regions has been viewed as a homogenous field, recent studies have demonstrated heterogeneous axonal dynamics and advances in GPCR-based fluorescent sensors permit direct observation of the local dynamics of NE at cellular scale. To investigate how the spatiotemporal dynamics of NE release in the PFC affect neuronal firing, we employed in-vivo two-photon imaging of layer 2/3 of PFC in order to observe fine-scale neuronal calcium and NE dynamics concurrently. We found that local and global NE fields can decouple from one another, providing a substrate for local NE spatiotemporal activity patterns. Optic flow analysis revealed putative release and reuptake events which can occur at the same location, albeit at different times, indicating the potential to create a heterogeneous NE field. Utilizing generalized linear models, we demonstrated that cellular Ca2+ fluctuations are influenced by both the local and global NE field. However, during periods of local/global NE field decoupling, the local field drives cell firing dynamics rather than the global field. These findings underscore the significance of localized, phasic NE fluctuations for structuring cell firing, which may provide local neuromodulatory control of cortical activity.

neuroscience↗

bioRxiv2022

5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early clinical studies. However relatively little is known about the behavioral effects and neural mechanisms of 5-MeO-DMT in animal models. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.

neuroscience↗

bioRxiv2022

Prefrontal norepinephrine represents a threat prediction error under uncertainty

Animals must learn to predict varying threats in the environment to survive by enacting defensive behaviors. Dopamine is involved in the prediction of rewards, encoding a reward prediction error in a similar manner to temporal difference learning algorithm. However, the corresponding molecular and computational form of threat prediction errors is not as well-characterized, although norepinephrine and other neuromodulators and neuropeptides participate in fear learning. Here, we utilized fluorescent norepinephrine recordings over the course of fear learning in concert with reinforcement learning modeling to identify its role in the prediction of threat. By varying timing and sensory uncertainty in the formation of threat associations, we were able to define a precise computational role for norepinephrine in this process. Norepinephrine release approximates the strength of fear associations, and its temporal dynamics are compatible with a prediction error signal. Intriguingly, the release of norepinephrine is influenced by time and sensory feedback, serving as an antithesis of the classical reward prediction error role of dopamine. Thus, these results directly demonstrate a combined cognitive and affective role of norepinephrine in the prediction of threat, with implications for neuropsychiatric disorders such as anxiety and PTSD.

neuroscience↗

bioRxiv2019

A computational model for learning from repeated trauma

AbstracTraumatic events can lead to lifelong inflexible adaptations in threat perception and behavior which characterize posttraumatic stress disorder (PTSD). This process involves associations between sensory cues and internal states of threat and then generalization of the threat responses to previously neutral cues. However, most formulations neglect adaptations to threat that are not specific to those associations. In order to incorporate non-associative responses to threat, we propose a computational theory of PTSD based on adaptation to the frequency of traumatic events using a reinforcement learning momentum model. Recent threat prediction errors generate momentum that influences subsequent threat perception in novel contexts. This model fits data acquired from a mouse model of PTSD, in which unpredictable footshocks in one context accelerate threat learning in a novel context. The theory is also consistent with epidemiological data showing that PTSD incidence increases with the number of traumatic events, as well as the disproportionate impact of early life trauma. Since the theory proposes that PTSD relates to the average of recent threat prediction errors rather than the strength of a specific association, it makes novel predictions for the treatment of PTSD.

animal behavior and cognition↗