Biology subjects

Witten, I.

Publications and source records attributed to Witten, I..

17 recordsLinked to original sources

bioRxiv2025

Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ9-THC Impairment

How {Delta}9-tetrahydrocannabinol (THC) impairs natural behaviors in mice remains unknown. We developed a video-monitored behavioral platform with machine learning classifiers to unravel discrete changes in natural mouse behaviors. THC infusion into the medial prefrontal cortex (mPFC) disrupted walking kinematic features characteristic of impairment responses. THC predominantly increased mPFC GABAergic activity preceding walk initiation shifting the mPFC excitatory/inhibitory (E/I) balance. Pose-defined closed loop photo-stimulation of mPFC GABAergic neurons demonstrated that THC exacerbates selected parameters of motor impairment. Surprisingly, THC also induced a time locked, movement-induced, transient potentiation of mPFC endocannabinoid (eCB) release and ensuing CB1R-mediated synaptic inhibition. Here we establish that THC-modifies mPFC E/I balance to excitation via dynamic changes in eCB release which acts to induce behavioral impairment.

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bioRxiv2025

Striatal pathways oppositely shift cortical activity along the decision axis

The cortex and basal ganglia are organized into multiple parallel loops that serve motor, limbic, and cognitive functions. The classic model of cortico-basal ganglia interactions posits that within each loop, the direct pathway of the basal ganglia activates the cortex and the indirect pathway inhibits it1-3. While this model has found support in the motor domain4,5, whether opponent control by the two pathways extends to the cognitive domain remains unknown. Here, we record from anterior cingulate cortex (ACC) and dorsomedial striatum (DMS) while inhibiting direct or indirect pathway neurons in DMS, as mice perform an accumulation-of-evidence task6-10. Inconsistent with the classic model, the manipulations do not produce opponent changes in overall ACC activity. Instead, the pathways exert opponent influence over a subpopulation of ACC neurons that encode accumulated sensory evidence, the task-relevant decision variable. The direction of the modulation depends on a neurons tuning to ipsilateral versus contralateral evidence, such that the two pathways generate opponent shifts in coding specifically along the decision axis. Thus, our results uncover unexpected specificity in the effects of basal ganglia pathways on the cortex, with the two pathways of the DMS exerting opponent control not on overall activity but on coding of the relevant task variable. This functional specificity may extend to other basal ganglia loops to support different aspects of adaptive behavior, with the pathways serving a general role in selecting and shifting cortical representations to subserve circuit-specific functions.

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bioRxiv2024

Prioritizing replay when future goals are unknown

Although hippocampal place cells replay nonlocal trajectories, the computational function of these events remains controversial. One hypothesis, formalized in a prominent reinforcement learning account, holds that replay plans routes to current goals. However, recent puzzling data appear to contradict this perspective by showing that replayed destinations lag current goals. These results may support an alternative hypothesis that replay updates route information to build a "cognitive map." Yet no similar theory exists to formalize this view, it is unclear how such a map is represented or what role replay plays in computing it. We address these gaps by introducing a theory of replay that learns a map of routes to candidate goals, before reward is available or when its location may change. Replay is then focused on current goals (as with planning) and/or potential future goals (like a map), depending on the animals expectations about future goal switching. Our work thus generalizes the planning account to capture a general map-building function for replay, reconciling it with data, and revealing an unexpected relationship between the seemingly distinct hypotheses. The theory offers a unifying explanation why data from tasks with different goal dynamics have seemingly supported different hypotheses for the function of replay, and suggests new predictions for experiments testing these effects. Graphical Abstract HighlightsO_LIA reinforcement learning model explains how to use replay to build a cognitive map for navigation C_LIO_LIMap-building replay explains recent replay data from goal-switching tasks that stymie previous theoretical accounts C_LIO_LIModel predicts replay in the absence of rewards as well as sensitivity of replay to goal statistics C_LIO_LIModel suggests planning-like replay is a special case of map-like replay C_LI

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bioRxiv2024

Pre-existing visual responses in a projection-defined dopamine population explain individual learning trajectories

Learning a new task is challenging because the world is high dimensional, with only a subset of features being reward-relevant. What neural mechanisms contribute to initial task acquisition, and why do some individuals learn a new task much more quickly than others? To address these questions, we recorded longitudinally from dopamine (DA) axon terminals in mice learning a visual task. Across striatum, DA responses tracked idiosyncratic and side-specific learning trajectories. However, even before any rewards were delivered, contralateral-side-specific visual responses were present in DA terminals only in the dorsomedial striatum (DMS). These pre-existing responses predicted the extent of learning for contralateral stimuli. Moreover, activation of these terminals improved contralateral performance. Thus, the initial conditions of a projection-specific and feature-specific DA signal help explain individual learning trajectories. More broadly, this work implies that functional heterogeneity across DA projections serves to bias target regions towards learning about different subsets of task features, providing a mechanism to address the dimensionality of the initial task learning problem.

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bioRxiv2023

Differences in an aversive teaching signal produce brainwide and behavioral substrates of susceptibility

Some individuals are susceptible to the experience of chronic stress and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After, but not before, chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and activation of the LHb during stress biases mice towards susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.

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bioRxiv2023

Overlapping representations of food and social stimuli in VTA dopamine neurons

Dopamine neurons of the ventral tegmental area (VTADA) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear if the same or different VTADA neurons encode these different stimuli. To address this question, we performed 2-photon calcium imaging in mice presented with food and conspecifics, and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience further increased the proportion of neurons that respond to both stimuli, implying that modifying motivation for one stimulus affects responses to both stimuli. In addition, single-nucleus RNA sequencing revealed significant co-expression of feeding- and social-hormone related genes in individual VTADA neurons. Taken together, our functional and transcriptional data suggest overlapping VTADA populations underlie food and social motivation.

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bioRxiv2022

Independent inhibitory control mechanisms for aggressive motivation and action

Social behaviors, like other motivated behaviors, frequently consist of a flexible motivated-seeking or approach phase followed by social action. Dysregulated social behavior may arise from changes to motivation, wherein individuals fail to enter a motivated seeking state, or may be in the execution of the social action itself. However, it is unclear how the brain generates and gates this flexible motivation-to-action sequence, and whether aggressive motivation and action are controlled by separate circuit mechanisms. Here, we record populations of neurons in the ventromedial hypothalamus ventrolateral area (VMHvl) of male mice at cellular resolution during "free" aggression and also during an aggression operant task, where the behaviors that precede attack are stereotyped. We find that this population encodes the temporal sequence of aggressive motivation to action and that the temporal selectivity of neurons is invariant to differences in motivated behavior. To test whether motivation and action could be independently regulated, we focused on two key inhibitory inputs to the VMHvl: a source of local inhibition (VMHvl shell) and the primary source of long-range inhibition (the medial preoptic area, MPO). While we find that the VMHvl receives broad monosynaptic inhibitory input from both inputs, optogenetic perturbation of these inputs during recording reveals temporal selectivity during aggressive motivation and action, suggesting specificity of function. Encoding models applied to population calcium recordings of these inhibitory inputs during naturalistic social interactions and during the social operant task further reveal that these inputs have different temporal dynamics during aggression: VMHvl shellvgat+ activity peaks at the start of aggressive interactions, while MPO-VMHvlvgat+ activity peaks at behaviorally aligned endpoints of aggressive interactions. Finally, using closed-loop optogenetic stimulation timed to specific phases of the aggression-operant task, we find a double-dissociation of the effects on aggressive motivation and action: activation of MPO-VMHvlvgat+, even briefly and temporally distant from the initiation of aggression, produces long-lasting motivational deficits, delaying the initiation of aggression and generating behaviors consistent with an unmotivated state. In contrast, activation of VMHvl shellvgat+ produces acute action-related deficits, causing an exit from an attack state. Fitting a Hidden Markov Model (HMM) to behavior further corroborates these findings by showing that MPO-VMHvlvgat+ stimulation prolongs a low motivation state and VMHvl shellvgat+ promotes exit from an attack state. Together, these data demonstrate how separable inhibitory circuits in the hypothalamus can independently gate the motivational and action phases of aggression through a single locus of control.

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bioRxiv2022

Behavioral and dopaminergic signatures of resilience

Chronic stress can have lasting adverse consequences in some individuals, yet others are resilient to the same stressor1,2. While previous work found differences in the intrinsic properties of mesolimbic dopamine (DA) neurons in susceptible and resilient individuals after stress was over;3-10 the causal links between DA activity during stress, dynamic stress-evoked behavior, and individual differences in susceptibility and resilience are not known. Here, we record behavior and neural activity in DA projections to the nucleus accumbens (NAc, signals reward11-14) and to the tail striatum (TS, signals threat15-18) during a multiday chronic social defeat paradigm and discover behavioral and neural signatures of resilience. Using supervised and unsupervised behavioral quantification, we find that resilient and susceptible individuals employ different behavioral strategies during stress. In addition, NAc-DA (but not TS-DA) activity is higher in the proximity of the aggressor in resilient mice, consistent with a greater subjective value of the aggressor. Moreover, NAc-DA tends to be elevated at the onset of fighting back in resilient mice and at the offset of attacks in susceptible mice. To test whether DA activation during defeat can generate resilience, and if its timing with respect to behavior is critical, we performed optogenetic stimulation of NAc-DA in open-loop (randomly timed) during defeat or timed to specific behaviors using real-time pose-tracking and behavioral classification. We find that both open-loop DA activation and fighting-back-timed activation promote resilience, in both cases reorganizing behavior during defeat toward resilience-associated patterns. Attack offset-timed activation promotes avoidance during defeat but does not promote susceptibility afterwards. Together, these data suggest a model whereby, during stress, DA in the NAc can increase resilience primarily by elevating the subjective value of the stressor rather than by reinforcing particular stress-responsive behaviors.

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bioRxiv2021

Strong and opponent contributions of dorsomedial striatal pathways to behavior depends on cognitive demands and task strategy

A classic view of the striatum holds that activity in direct and indirect pathways oppositely modulates motor output. Whether this involves direct control of movement, or reflects a cognitive process underlying movement, remains unresolved. Here we find that strong, opponent control of behavior by the two pathways of the dorsomedial striatum (DMS) depends on the cognitive requirements of a task. Furthermore, a latent state model (a hidden markov model with generalized linear model observations) reveals that--even within a single task--the contribution of the two pathways to behavior is state-dependent. Specifically, the two pathways have large contributions in one of two states associated with a strategy of evidence accumulation, compared to a state associated with a strategy of repeating previous choices. Thus, both the demands imposed by a task, as well as the internal state of mice when performing a task, determine whether DMS pathways provide strong and opponent control of behavior.

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bioRxiv2020

Inferring spikes from calcium imaging in dopamine neurons

Calcium imaging has led to discoveries about neural correlates of behavior in subcortical neurons, including dopamine (DA) neurons. However, spike inference methods have not been tested in most populations of subcortical neurons. To address this gap, we simultaneously performed calcium imaging and electrophysiology in DA neurons in brain slices, and applied a recently developed spike inference algorithm to the GCaMP fluorescence. This revealed that individual spikes can be inferred accurately in this population. Next, we inferred spikes in vivo from calcium imaging from these neurons during Pavlovian conditioning, as well as during navigation in virtual reality. In both cases, we quantitatively recapitulated previous in vivo electrophysiological observations. Our work provides a validated approach to infer spikes from calcium imaging in DA neurons, and implies that aspects of both tonic and phasic spike patterns can be recovered.

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bioRxiv2020

A comparison of dopaminergic and cholinergic populations reveals unique contributions of VTA dopamine neurons to short-term memory

We systematically compared the contribution of two dopaminergic and two cholinergic ascending populations to a spatial short-term memory task in rats. In ventral tegmental area dopamine (VTA-DA) and nucleus basalis cholinergic (NB-ChAT) populations, trial-by-trial fluctuations in activity during the delay period related to performance with an inverted-U, despite the fact that both populations had low activity during that time. Transient manipulations revealed that only VTA-DA neurons, and not the other three populations we examined, contributed causally and selectively to short-term memory. This contribution was most significant during the delay period, when both increases or decreases in VTA-DA activity impaired short-term memory. Our results reveal a surprising dissociation between when VTA-DA neurons are most active and when they have the biggest causal contribution to short-term memory, while also providing new types of support for classic ideas about an inverted-U relationship between neuromodulation and cognition.

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bioRxiv2020

A standardized and reproducible method to measure decision-making in mice

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We designed a task for head-fixed mice that combines established assays of perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be successfully reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path towards achieving reproducibility in neuroscience through collaborative open-science approaches.

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bioRxiv2020

Dissociable roles of central striatum and anterior lateral motor area in initiating and sustaining naturalistic behavior

Although much is known about how corticostriatal circuits mediate behavioral selection, most previous work has been conducted in highly trained animals engaged in instrumental tasks. Understanding how corticostriatal circuits mediate behavioral selection and initiation in a naturalistic setting is critical to understanding how the brain chooses and executes behavior in unconstrained situations. Central striatum (CS), an understudied region that lies in the middle of the motor-limbic topography, is well-poised to play an important role in these processes since its main cortical inputs (Corbit et al., 2019) have been implicated in behavioral flexibility (lateral orbitofrontal cortex (Kim and Ragozzino, 2005)) and response preparation (anterior lateral motor area, ALM) (Li et al., 2015), However, although CS activity has been associated with conditioned grooming behavior in transgenic mice (Burguiere et al., 2013), the role of CS and its cortical inputs in the selection of spontaneous behaviors has not been explored. We therefore studied the role of CS corticostriatal circuits in behavioral selection in an open field context. Surprisingly, using fiber photometry in this unconstrained environment, we found that population calcium activity in CS was specifically increased at onset of grooming, and not at onset of other spontaneous behaviors such as rearing or locomotion. Supporting a potential selective role for CS in the initiation of grooming, bilateral optogenetic stimulation of CS evoked immediate onset grooming-related movements. However, these movements resembled subcomponents of grooming behavior and not full-fledged grooming bouts, suggesting that additional input(s) are required to appropriately sequence and sustain this complex motor behavior once initiated. Consistent with this idea, optogenetic stimulation of CS inputs from ALM generated sustained grooming responses that evolved on a time-course paralleling CS activation monitored using single-cell calcium imaging. Furthermore, fiber photometry in ALM demonstrated a gradual ramp in calcium activity that peaked at time of grooming termination, supporting a potential role for ALM in encoding length of this spontaneous sequenced behavior. Finally, dual color dual region fiber photometry indicated that CS activation precedes ALM during naturalistic grooming sequences. Taken together, these data support a novel model in which CS activity is sufficient to initiate grooming behavior, but ALM activity is necessary to sustain and encode the length of grooming bouts. Thus, the use of an unconstrained behavioral paradigm has allowed us to uncover surprising roles for CS and ALM in the initiation and maintenance of spontaneous sequenced behaviors.

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bioRxiv2018

Specialized and spatially organized coding of sensory, motor, and cognitive variables in midbrain dopamine neurons

There is increased appreciation that dopamine (DA) neurons in the midbrain respond not only to reward 1,2 and reward-predicting cues 1,3,4, but also to other variables such as distance to reward 5, movements 6-11 and behavioral choices 12-15. Based on these findings, a major open question is how the responses to these diverse variables are organized across the population of DA neurons. In other words, do individual DA neurons multiplex multiple variables, or are subsets of neurons specialized in encoding specific behavioral variables? The reason that this fundamental question has been difficult to resolve is that recordings from large populations of individual DA neurons have not been performed in a behavioral task with sufficient complexity to examine these diverse variables simultaneously. To address this gap, we used 2-photon calcium imaging through an implanted lens to record activity of >300 midbrain DA neurons in the VTA during a complex decision-making task. As mice navigated in a virtual reality (VR) environment, DA neurons encoded an array of sensory, motor, and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioral variables, in addition to encoding reward. These functional clusters were spatially organized, such that neighboring neurons were more likely to be part of the same cluster. Taken together with the topography between DA neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by DA neurons.

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bioRxiv2018

Dopamine modulation of prefrontal cortex activity is manifold and operates at multiple temporal and spatial scales

While the function of dopamine in subcortical structures is largely limited to reward and movement, dopamine neurotransmission in the prefrontal cortex (PFC) is critical to a multitude of temporally and functionally diverse processes such as attention, working memory, behavioral flexibility, action selection, and stress adaptation. How does dopamine influence PFC computation of multiple temporally diverse functions? Here we find causation between sustained and burst patterns of phasic dopamine neuron activation and contemporaneous modulation of PFC neuronal activity at multiple spatio-temporal scales. These include a multidirectional and weak impact on individual PFC neuron rate activity and a robust influence on coordinated ensemble activity, gamma oscillations, and gamma-theta coupling that persisted for minutes. In addition, PFC network responses to burst pattern of dopamine firing were selectively strengthened in behaviorally active states. Thus, dopamine modulation of PFC is spatiotemporally diverse and is dictated by the pattern of dopamine neuron activation and behavioral state. These findings provide insight on the multiplex pattern of modulation by dopamine that may influence PFC computation of temporally diverse functions.

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bioRxiv2017

An accumulation-of-evidence task using visual pulses for mice navigating in virtual reality

The gradual accumulation of sensory evidence is a crucial component of perceptual decision making, but its neural mechanisms are still poorly understood. Given the wide availability of genetic and optical tools for mice, they can be useful model organisms for the study of these phenomena; however, behavioral tools are largely lacking. Here, we describe a new evidence-accumulation task for head-fixed mice navigating in a virtual reality environment. As they navigate down the stem of a virtual T-maze, they see brief pulses of visual evidence on either side, and retrieve a reward on the arm with the highest number of pulses. The pulses occur randomly with Poisson statistics, yielding a diverse yet well-controlled stimulus set, making the data conducive to a variety of computational approaches. A large number of mice of different genotypes were able to learn and consistently perform the task, at levels similar to rats in analogous tasks. They are sensitive to side differences of a single pulse, and their memory of the cues is stable over time. Moreover, using non-parametric as well as modeling approaches, we show that the mice indeed accumulate evidence: they use multiple pulses of evidence from throughout the cue region of the maze to make their decision, albeit with a small overweighting of earlier cues, and their performance is affected by the magnitude but not the duration of evidence. Additionally, analysis of the mice's running patterns revealed that trajectories are fairly stereotyped yet modulated by the amount of sensory evidence, suggesting that the navigational component of this task may provide a continuous readout correlated to the underlying cognitive variables. Our task, which can be readily integrated with state-of-the-art techniques, is thus a valuable tool to study the circuit mechanisms and dynamics underlying perceptual decision making, particularly under more complex behavioral contexts.

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bioRxiv2017

Combined social and spatial coding in a descending projection from the prefrontal cortex

Social interactions are crucial to the survival and well-being of all mammals, including humans. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant, nor how they contribute. We found that the PL contains anatomically and molecularly distinct subpopulations of neurons that target 3 downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), the amygdala, and the ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased preference for a social target, suggesting an unique contribution of this population to social behavior. To determine what information PL-NAc neurons convey, we recorded selectively from them, and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially-specific inhibition of these neurons prevented the formation of a social-spatial association at the inhibited location. In contrast, spatially nonspecific inhibition did not affect social behavior. Thus, the unexpected combination of social and spatial information within the PL-NAc population appears to support socially motivated behavior by enabling the formation of social-spatial associations.

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