Biology subjects

Tye, K. M.

Publications and source records attributed to Tye, K. M..

14 recordsLinked to original sources

bioRxiv2025

Social Exclusion Amplifies Behavioral Responses to Physical Pain via Insular Neuromodulation

The "Pain Overlap Theory" (1) proposes that the experience of social pain overlaps with and amplifies the experience of physical pain by sharing parts of the same underlying processing systems (2-6). In humans, the insular cortex has been implicated in this overlap of physical and social pain, but a mechanistic link has not been made (2,4,5,7-9). To determine whether social pain can subsequently impact responses to nociceptive stimuli via convergent electrical signals (spikes) or convergent chemical signals (neuromodulators), we designed a novel Social Exclusion paradigm termed the Fear of Missing Out (FOMO) Task which facilitates a mechanistic investigation in mice. We found that socially-excluded mice display more severe responses to physical pain, disrupted valence encoding, and impaired neural representations of nociceptive stimuli. We performed a systematic biosensor panel and found that endocannabinoid and oxytocin signaling in the insular cortex have opposing responses during trials where mice were attending or not attending to the Social Exclusion events respectively, demonstrating distinct neuromodulatory substrates that underpin different states of Social Exclusion. We also found that intra-insular blockade of oxytocin signaling increased the response to physical pain following Social Exclusion. Together these findings suggest Social Exclusion effectively alters physical pain perception using neuromodulatory signaling in the insular cortex.

neuroscience↗

bioRxiv2025

Separable Dorsal Raphe Dopamine Projections mediate the Facets of Loneliness-like state

Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT), which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRNDAT projections - to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) - play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photostimulation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRNDAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRNDAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRNDAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli- suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.

neuroscience↗

bioRxiv2024

Control of innate olfactory valence by segregated cortical amygdala circuits

Animals exhibit innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance responses. The posterolateral cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate attraction and aversion to odor. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express VGluT2 and posterior neurons express VGluT1. Activation of these respective cell types recapitulates appetitive and aversive behaviors, and chemogenetic inhibition reveals partial necessity for responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate attraction and aversion. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This suggests a novel amygdala circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct behaviors of opposing appetitive and aversive responses.

neuroscience↗

bioRxiv2024

An unbiased method to partition diverse neuronal responses into functional ensembles reveals interpretable population dynamics during innate social behavior

In neuroscience, understanding how single-neuron firing contributes to distributed neural ensembles is crucial. Traditional methods of analysis have been limited to descriptions of whole population activity, or, when analyzing individual neurons, criteria for response categorization varied significantly across experiments. Current methods lack scalability for large datasets, fail to capture temporal changes and rely on parametric assumptions. Theres a need for a robust, scalable, and non-parametric functional clustering approach to capture interpretable dynamics. To address this challenge, we developed a model-based, statistical framework for unsupervised clustering of multiple time series datasets that exhibit nonlinear dynamics into an a-priori-unknown number of parameterized ensembles called Functional Encoding Units (FEUs). FEU outperforms existing techniques in accuracy and benchmark scores. Here, we apply this FEU formalism to single-unit recordings collected during social behaviors in rodents and primates and demonstrate its hypothesis-generating and testing capacities. This novel pipeline serves as an analytic bridge, translating neural ensemble codes across model systems.

neuroscience↗

bioRxiv2023

Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking

Social isolation profoundly alters motivation and increases vulnerability to alcohol misuse in humans, yet the underlying neural mechanisms remain unclear. Here we show that isolation escalates alcohol drinking in male mice but suppresses it in females. Whole-cell recordings revealed that neurons in the basolateral amygdala projecting to the medial prefrontal cortex (BLA-mPFC) track alcohol intake in both sexes. Isolation increased BLA-mPFC excitability in males but decreased it in females, mirroring their opposite behavioral adaptations. Given this divergence, we focused subsequent mechanistic studies on males to isolate neural pathway-level drivers of escalated alcohol intake. Cellular-resolution calcium imaging showed that activity in BLA-mPFC neurons encodes and predicts alcohol drinking, and optogenetic activation of this pathway increased alcohol intake. Simultaneous optogenetics and calcium imaging revealed that BLA-mPFC stimulation enhanced mPFC neuronal responses to alcohol, mimicking isolation-induced activity patterns, while photoinhibition reduced drinking in isolated mice. Together, these findings identify a BLA-mPFC pathway mechanism through which social isolation reconfigures prefrontal processing to promote alcohol intake.

neuroscience↗

bioRxiv2022

Amygdalostriatal transition zone neurons encode sustained valence to direct conditioned behaviors

To ensure survival, the brain must rapidly identify threats and maintain defensive behaviors for as long as danger is present. The amygdala has been studied as a key site for fear responses, but responses to threat cues in amygdala neurons are largely transient and shorter in duration than defensive responses observed. Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of the circuits mediating fear responses. Using single-nucleus RNA sequencing (snRNA-seq), we demonstrate that the ASt is genetically distinct from adjacent striatal and amygdalar structures. In vivo electrophysiology and calcium imaging reveal that ASt neurons have robust, sustained responses to shock-predicting cues. Further, photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors, and optogenetic inhibition experiments show that Drd2+ ASt neurons are necessary for cue-conditioned fear responses. Our findings establish the ASt as a previously unappreciated yet critical structure for encoding learned associations and directing defensive behaviors.

neuroscience↗

bioRxiv2022

Thalamus sends information about arousal but not valence to the amygdala

RationaleThe basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. ObjectivesWe seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. MethodsHere, we use optogenetics to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. ResultsWe find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. ConclusionWe conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified. PrefaceIn tribute to Nadia Chaudhri, and her discoveries regarding how contexts can modulate the representation of cues in the amygdala (Sciascia et al., 2015), and other mesolimbic circuit components (Chaudhri et al., 2009, 2008; Valyear et al., 2020), here we explore what information processing precedes entry into the basolateral amygdala (BLA) from the thalamus and develop visualization approaches for exploring across-trial temporal dynamics in addition to within-trial population activity.

neuroscience↗

bioRxiv2022

Reward contingency gates selective cholinergic suppression of amygdala neurons

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward - even in prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex (PFC). Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic-receptor-signaling, while also facilitating firing in GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.

neuroscience↗

bioRxiv2021

Neuromodulators enable overlapping synaptic memory regimes and nonlinear transition dynamics in recurrent neural networks

Neuromodulators are critical controllers of neural states, with dysfunctions linked to various neuropsychiatric disorders. Although many biological aspects of neuromodulation have been studied, the computational principles underlying how neuromodulation of distributed neural populations controls brain states remain unclear. Compared with specific contextual inputs, neuromodulation is a single scalar signal that is broadcast broadly to many neurons. We model the modulation of synaptic weight in a recurrent neural network model and show that neuromodulators can dramatically alter the function of a network, even when highly simplified. We find that under structural constraints like those in brains, this provides a fundamental mechanism that can increase the computational capability and flexibility of a neural network. Diffuse synaptic weight modulation enables storage of multiple memories using a common set of synapses that are able to generate diverse, even diametrically opposed, behaviors. Our findings help explain how neuromodulators "unlock" specific behaviors by creating task-specific hyperchannels in the space of neural activities and motivate more flexible, compact and capable machine learning architectures. SignificanceNeuromodulation through the release of molecules like serotonin and dopamine provides a control mechanism that allows brains to shift into distinct behavioral modes. We use an artificial neural network model to show how the action of neuromodulatory molecules acting as a broadcast signal on synaptic connections enables flexible and smooth behavioral shifting. We find that individual networks exhibit idiosyncratic sensitivities to neuromodulation under identical training conditions, highlighting a principle underlying behavioral variability. Network sensitivity is tied to the geometry of network activity dynamics, which provides an explanation for why different types of neuromodulation (molecular vs direct current modulation) have different behavioral effects. Our work suggests experiments to test biological hypotheses and paths forward in the development of flexible artificial intelligence systems.

neuroscience↗

bioRxiv2020

AlphaTracker: A Multi-Animal Tracking and Behavioral Analysis Tool

The advancement of behavioral analysis in neuroscience has been aided by the development of computational tools1,2. Specifically, computer vision algorithms have emerged as a powerful tool to elevate behavioral research3,4. Yet fully automatic analysis of social behavior remains challenging in two ways. First, existing tools to track and analyze behavior often focus on single animals, not multiple, interacting animals. Second, many available tools are not developed for novice users and require programming experience to run. Here, we unveil a computer vision pipeline called AlphaTracker, which requires minimal hardware requirements and produces reliable tracking of multiple unmarked animals. An easy-to-use user interface further enables manual inspection and curation of results. We demonstrate the practical, real-time advantages of AlphaTracker through the study of multiple, socially-interacting mice.

animal behavior and cognition↗

bioRxiv2020

A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex

The prefrontal cortex encodes and stores numerous, often disparate, schemas and flexibly switches between them. Recent research on artificial neural networks trained by reinforcement learning has made it possible to model fundamental processes underlying schema encoding and storage. Yet how the brain is able to create new schemas while preserving and utilizing old schemas remains unclear. Here we propose a simple neural network framework based on a modification of the mixture of experts architecture to model the prefrontal cortexs ability to flexibly encode and use multiple disparate schemas. We show how incorporation of gating naturally leads to transfer learning and robust memory savings. We then show how phenotypic impairments observed in patients with prefrontal damage are mimicked by lesions of our network. Our architecture, which we call DynaMoE, provides a fundamental framework for how the prefrontal cortex may handle the abundance of schemas necessary to navigate the real world.

neuroscience↗

bioRxiv2019

Precision calcium imaging of dense neural populations via a cell body-targeted calcium indicator

Methods for one-photon fluorescent imaging of calcium dynamics in vivo are popular due to their ability to simultaneously capture the dynamics of hundreds of neurons across large fields of view, at a low equipment complexity and cost. In contrast to two-photon methods, however, one-photon methods suffer from higher levels of crosstalk between cell bodies and the surrounding neuropil, resulting in decreased signal-to-noise and artifactual correlations of neural activity. Here, we address this problem by engineering cell body-targeted variants of the fluorescent calcium indicator GCaMP6f. We screened fusions of GCaMP6f to both natural as well as engineered peptides, and identified fusions that localized GCaMP6f to within approximately 50 microns of the cell body of neurons in live mice and larval zebrafish. One-photon imaging of soma-targeted GCaMP6f in dense neural circuits reported fewer artifactual spikes from neuropil, increased signal-to-noise ratio, and decreased artifactual correlation across neurons. Thus, soma-targeting of fluorescent calcium indicators increases neuronal signal fidelity and may facilitate even greater usage of simple, powerful, one-photon methods of population imaging of neural calcium dynamics.

neuroscience↗

bioRxiv2018

Acute Food Deprivation Rapidly Modifies Valence-Coding Microcircuits in the Amygdala

In the quest for food, we may expend effort and increase our vulnerability to potential threats. Motivation to seek food is dynamic, varying with homeostatic need. What mechanisms underlie these changes? Basolateral amygdala neurons projecting to the nucleus accumbens (BLA[->]NAc) preferentially encode positive valence, whereas those targeting the centromedial amygdala (BLA[->]CeM) preferentially encode negative valence. Longitudinal in vivo two-photon calcium imaging revealed that BLA[->]NAc neurons were more active, while BLA[->]CeM neurons were less active, following just 1 day of food deprivation. Photostimulating BLA[->]CeM neurons inhibited BLA[->]NAc neurons at baseline, but food deprivation rapidly converted this inhibition into facilitation, supporting a model wherein BLA[->]NAc excitability mediates invigorated food-seeking behavior after deprivation. Indeed, inhibiting BLA[->]NAc reduced motivation for a caloric reinforcer in food deprived animals. Taken together, negative valence overrides positive valence processing in satiety, but changing homeostatic needs alter reward value via a rapid shift in the balance between projection-defined populations of BLA neurons.

neuroscience↗

bioRxiv2017

Acute stress induces long-lasting alterations in the dopaminergic system of female mice

Stress is a risk factor for many neuropsychiatric disorders, and the mesolimbic dopamine (DA) pathway is a crucial node of vulnerability. Despite the high prevalence of stress-related neuropsychiatric disorders in women, preclinical knowledge on the impact of stress on neural circuitry has predominantly been acquired in males. Here, we examine how a non-social stressor impacts the effect of DA neurotransmission on social and reward-related behaviors in female mice. Acute stress exposure attenuated the anti-social effects of photoinhibiting ventral tegmental area (VTA) DA neurons and transformed photoactivation of these cells into an anti-social signal. Fast-scan cyclic voltammetry (FSCV) revealed an enhancement in optogenetically-induced DA release after stress. 60 days after stress, mice showed distinct patterns of intra-cranial self-stimulation of VTA DA neurons. Our results reveal the impact stress exerts on females and show that neural and behavioral changes induced by acute stress exposure are still present months later.

neuroscience↗