Biology subjects

Warden, M. R.

Publications and source records attributed to Warden, M. R..

13 recordsLinked to original sources

bioRxiv2025

Oscillatory Control of Cortical Space as a Computational Dimension

Flexible cognition depends on the ability to represent and apply relevant information to the current task at hand. This allows the brain to interpret sensory input and guide behavior in a context-dependent manner. Recent work has proposed Spatial Computing as a mechanism for this flexibility, suggesting that task-related signals organize information processing through spatial patterns of oscillatory activity across the cortical surface. These patterns are proposed to act as "inhibitory stencils" that constrain where sensory-related information (the "content" of cognition) can be expressed in spiking activity. Here, we provide a comprehensive empirical test of Spatial Computing using multi-electrode recordings from the lateral prefrontal cortex in non-human primates performing a range of cognitive tasks (object working memory, sequence working memory, categorization). We found that alpha/beta oscillations encoded task-related information, were organized into spatial patterns that changed with task conditions, and inversely correlated with the spatial expression of sensory-related spiking activity. Furthermore, we found that alpha/beta oscillations reflected misattributions of task conditions and correlated with subjects trial-by-trial decisions. These findings validate core predictions of Spatial Computing suggesting that oscillatory dynamics not only gate information in time but also shape where in the cortex cognitive content is represented. This framework offers a unifying principle for understanding how the brain flexibly coordinates cognition through structured population dynamics.

neuroscience↗

bioRxiv2023

Ventromedial prefrontal parvalbumin neurons are necessary for initiating cued threat avoidance

The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.

neuroscience↗

bioRxiv2023

Male ejaculation phasically activates dorsal raphe serotonin neurons in mating female mice

Sexual stimulation triggers changes in female physiology and behavior, including sexual satiety and preparing the uterus for pregnancy. Serotonin is an important regulator of reproductive physiology and sexual receptivity, but the relationship between sexual stimulation and serotonin neural activity in females is poorly understood. Here, we investigated dorsal raphe serotonin neural activity in females during sexual behavior. We found that serotonin neural activity in mating females peaked specifically upon male ejaculation, and remained elevated above baseline until disengagement. Artificial intravaginal mechanical stimulation was sufficient to elicit increased 5-HT neural activity but the delivery of ejaculatory fluids was not. Distal penis erectile enlargement ("penile cupping") at ejaculation and forceful expulsion of ejaculatory fluid each provided sufficient mechanical stimulation to elicit serotonin neuron activation. Our study identifies a female ejaculation-specific signal in a major neuromodulatory system and shows that intravaginal mechanosensory stimulation is necessary and sufficient to drive this signal.

neuroscience↗

bioRxiv2023

Coding of time with non-linear mixed selectivity in Prefrontal Cortex ensembles

Previous work has identified stimulus specific time cells as a potential mechanism for working memory maintenance. It has been proposed that populations of stimulus specific sequences of cells could support memory for many items in a list over long periods of time. This would require information about one stimulus to persist after the presentation of subsequent stimuli. However, it is not known if sequences triggered by one stimulus persist past the presentation of additional stimuli. It is possible that each new stimulus terminates preceding sequences, making memory for multiple stimuli impossible. To investigate this question, we utilized a data set originally published by (Warden & Miller, 2010), studying the firing of monkey prefrontal neurons during short lists of stimuli. We were able to decode "what happened when" throughout the list, using linear discriminant analysis. Additionally, we were able to decode the first stimulus after the presentation of the second stimulus. Furthermore, we found that stimulus modulated sequences of cells, with discrete temporal fields, continue after the second item was presented. Much of the information about the previous item was carried by neurons that responded to conjunctions of stimuli and the timing of late-firing cells was synchronized to the firing of the second stimulus rather than the first. These properties falsify a simple linear model of sequential time cells. These results suggest that non-linear mixed selectivity extends to continuous variables such as time, but that in this experiment at least, only the timing of the most recent stimulus was explicitly maintained in ongoing firing.

neuroscience↗

bioRxiv2022

Reproductive state switches the valence of male urinary pheromones in female mice

Internal states shape responses to sensory stimuli. Mammalian female reproductive states are understudied considering they are one of the most regular state changes in the animal kingdom. Here we examine female house mouse preferences toward male odors across the reproductive states of estrus and late-stage pregnancy. In house mice, urine scent marks are salient social odors that convey information about the sex and identity of individuals by major urinary proteins (MUPs). Males secrete a sex-specific pheromonal protein called darcin (MUP20). Additionally, genetically diverse mice secrete unique combinations of MUPs used in individual recognition. Prior work has revealed that male odors are powerful social stimuli for female mice, yet we have a limited understanding of how the valence of such odors change across reproductive states. We discovered a valence shift among estrus and pregnant females toward novel male urine, in which estrus females exhibit preference and pregnant females show strong avoidance. This valence switch also occurs toward darcin alone, providing further support for darcin as a strong sexual signal. However, when presented with familiar male urine, the approach-avoidance response disappears, even when additional darcin is added. In contrast, when an existing identity protein (MUP11) is added to familiar male urine the approach-avoidance response is recovered. This indicates that darcin in the absence of other identity information denotes a novel male and that familiar identity information present in male urine is sufficient to modify responses to darcin. Our findings suggest that the sex and identity information encoded by MUPs are likely processed via distinct, and potentially opposing pathways, that modulate responses toward complex social odor blends. Furthermore, we identify a state-modulated shift in decision-making toward social odors and propose a neural circuit model for this flow of information. These data underscore the importance of physiological state and signal context for interpreting the meaning and importance of social odors.

animal behavior and cognition↗

bioRxiv2022

Reduced variability of bursting activity during working memory

Working memories have long been thought to be maintained by persistent spiking. However, mounting evidence from multiple-electrode recording (and single-trial analyses) shows that the underlying spiking is better characterized by intermittent bursts of activity. A counterargument suggested this intermittent activity is at odds with observations that spike-time variability reduces during task performance. However, this counterargument rests on assumptions, such as randomness in the timing of the bursts, that may not be correct. Thus, we analyzed spiking and LFPs from the prefrontal cortex (PFC) of monkeys to determine if task-related reductions in variability can co-exist with intermittent spiking. We found that it does because both spiking and associated gamma bursts were task-modulated, not random. In fact, the task-related reduction in spike variability could be explained by a related reduction in gamma burst variability. Our results provide further support for the intermittent activity models of working memory as well as novel mechanistic insights into how spike variability is reduced during cognitive tasks.

neuroscience↗

bioRxiv2022

Dynamic changes to signal allocation rules in response to variable social environments in house mice

Male house mice use metabolically costly urine marks in intrasexual competition and mate attraction. Given the high costs of signaling and the depletable nature of urine reserves, males should dynamically modulate signal allocation as the social landscape is updated with new information. We investigate which aspects of male urine marking behavior are static or dynamic in light of changing social environments. To do this, we use thermal imaging to capture spatiotemporal data of urine deposition decisions. This novel method reveals fine-scale variation in urinary motor patterns in response to competition and social odors. Males demonstrate striking winner-loser effects in both the total allocation effort and temporal dynamics of scent marking. We find that competitive experience primes key temporal features of signal allocation and modulates responses to familiar and unfamiliar male scents. Males adjust their signaling effort, mark latency, and scent mark rhythm, depending on the scent identities present in the environment. Winners dramatically increase marking effort toward unfamiliar compared to familiar male scent, consistent with a dear enemy effect. Losers, in contrast, greatly reduce marking to unfamiliar scent but increase marking effort to the scent of their familiar rival, consistent with a nasty neighbor effect. Counter to the high lability of many features, the initial signal investment pattern influences allocation decisions days later, revealing the possibility of alternative scent mark strategies among competitive males. Thus, different features of urine mark signal allocation vary in responsiveness to fluctuating social landscapes, suggesting there are multiple distinct behavioral modules underlying marking behavior.

ecology↗

bioRxiv2021

Tonic activity in lateral habenula neurons promotes disengagement from reward-seeking behavior

Survival requires both the ability to persistently pursue goals and the ability to determine when it is time to stop, an adaptive balance of perseverance and disengagement. Neural activity in the lateral habenula (LHb) has been linked to aversion and negative valence, but its role in regulating the balance between reward-seeking and disengaged behavioral states remains unclear. Here, we show that LHb neural activity is tonically elevated during minutes-long disengagements from reward-seeking behavior, whether due to repeated reward omission or following sufficient consumption of reward. Further, we show that LHb inhibition extends ongoing reward-seeking behavioral states but does not prompt re-engagement. We find no evidence for similar tonic activity fluctuations in ventral tegmental area (VTA) dopamine neurons. Our findings implicate the LHb as a key mediator of disengagement from reward-seeking behavior in multiple contexts and argue against the idea that the LHb contributes to decisions solely by signaling aversion.

neuroscience↗

bioRxiv2021

A Hot-Coal theory of Working Memory

Working memory (WM) allows us to selectively remember and flexibly control a limited amount of information. Earlier work has suggested WM control is achieved by interactions between bursts of beta and gamma oscillations. The emerging question is how beta and gamma bursting, reflecting coherent activity of hundreds of thousands of neurons, can underlie selective control of individual items held in WM? Here, we propose a principle for how such selective control might be achieved on the neural network level. It relies on spatial computing, which suggests that beta and gamma interactions cause item-specific activity to flow spatially across the network over the course of a task. This way, control-related information about, for instance, item order can be retrieved from the spatial activity independent of the detailed recurrent connectivity that gives rise to the item-specific activity itself. The spatial flow should in turn be reflected in low-dimensional activity shared by many neurons. We test predictions of the proposed spatial computing paradigm by analysing control-related as well as item-specific activity in local field potentials and neuronal spiking from prefrontal cortex of rhesus macaques performing four WM tasks. As predicted, we find that the low-dimensional activity has a spatial component from which we can read out control-related information. These spatial components were stable over multiple sessions and did not depend on the specific WM items being used. We hypothesize that spatial computing can facilitate generalization and zero-shot learning by utilizing spatial component as an additional information encoding dimension. This offers a new perspective on the functional role of low-dimensional activity that tends to dominate cortical activity.

neuroscience↗

bioRxiv2020

Ramping activity in midbrain dopamine neurons signifies the use of a cognitive map

Journeys to novel and familiar destinations employ different navigational strategies. The first drive to a new restaurant relies on map-based planning, but after repeated trips the drive is automatic and guided by local environmental cues1,2. Ventral striatal dopamine rises during navigation toward goals and reflects the spatial proximity and value of goals3, but the impact of experience, the neural mechanisms, and the functional significance of dopamine ramps are unknown4,5. Here, we used fiber photometry6-8 to record the evolution of activity in midbrain dopamine neurons as mice learned a variety of reward-seeking tasks, starting recordings before training had commenced and continuing daily for weeks. When mice navigated through space toward a goal, robust ramping activity in dopamine neurons appeared immediately - after the first rewarded trial on the first training day in completely naive animals. In this task spatial cues were available to guide behavior, and although ramps were strong at first, they gradually faded away as training progressed. If instead mice learned to run a fixed distance on a stationary wheel for reward, a task that required an internal model of progress toward the goal, strong dopamine ramps persisted indefinitely. In a passive task in which a visible cue and reward moved together toward the mouse, ramps appeared and then faded over several days, but in an otherwise identical task with a stationary cue and reward ramps never appeared. Our findings provide strong evidence that ramping activity in midbrain dopamine neurons reflects the use of a cognitive map9,10 - an internal model of the distance already covered and the remaining distance until the goal is reached. We hypothesize that dopamine ramps may be used to reinforce locations on the way to newly-discovered rewards in order to build a graded ventral striatal value landscape for guiding routine spatial behavior.

neuroscience↗

bioRxiv2019

Quantitative analysis of 1300-nm three-photon calcium imaging in the mouse brain

1300-nm three-photon calcium imaging has emerged as a useful technique to allow calcium imaging in deep brain regions. Application to large-scale neural activity imaging entails a careful balance between recording fidelity and tissue heating. We calculated and experimentally verified the excitation pulse energy to achieve the minimum photon count required for the detection of calcium transients in GCaMP6s-expressing neurons for 920-nm two-photon and 1320-nm three-photon excitation, respectively. Brain tissue heating by continuous three-photon imaging was simulated with Monte Carlo method and experimentally validated with immunohistochemistry. We observed increased immunoreactivity with 150 mW excitation power at 1.0- and 1.2-mm imaging depths. Based on the data, we explained how three-photon excitation achieves better calcium imaging fidelity than two-photon excitation in the deep brain and quantified the imaging depth where three-photon microscopy should be applied. Our analysis presents a translatable model for the optimization of three-photon calcium imaging based on experimentally tractable parameters.

neuroscience↗

bioRxiv2017

Hebbian Learning in a Random Network Captures Selectivity Properties of Prefrontal Cortex

Complex cognitive behaviors, such as context-switching and rule-following, are thought to be supported by prefrontal cortex (PFC). Neural activity in PFC must thus be specialized to specific tasks while retaining flexibility. Nonlinear mixed selectivity is an important neurophysiological trait for enabling complex and context-dependent behaviors. Here we investigate (1) the extent to which PFC exhibits computationally relevant properties such as mixed selectivity and (2) how such properties could arise via circuit mechanisms. We show that PFC cells recorded from male and female rhesus macaques during a complex task show a moderate level of specialization and structure that is not replicated by a model wherein cells receive random feedforward inputs. While random connectivity can be effective at generating mixed selectivity, the data shows significantly more mixed selectivity than predicted by a model with otherwise matched parameters. A simple Hebbian learning rule applied to the random connectivity, however, increases mixed selectivity and allows the model to match the data more accurately. To explain how learning achieves this, we provide analysis along with a clear geometric interpretation of the impact of learning on selectivity. After learning, the model also matches the data on measures of noise, response density, clustering, and the distribution of selectivities. Of two styles of Hebbian learning tested, the simpler and more biologically plausible option better matches the data. These modeling results give intuition about how neural properties important for cognition can arise in a circuit and make clear experimental predictions regarding how various measures of selectivity would evolve during animal training.\n\nSignificance StatementPrefrontal cortex (PFC) is a brain region believed to support the ability of animals to engage in complex behavior. How neurons in this area respond to stimuli--and in particular, to combinations of stimuli (\"mixed selectivity\")--is a topic of interest. Despite the fact that models with random feedforward connectivity are capable of creating computationally-relevant mixed selectivity, such a model does not match the levels of mixed selectivity seen in the data analyzed in this study. Adding simple Hebbian learning to the model increases mixed selectivity to the correct level and makes the model match the data on several other relevant measures. This study thus offers predictions on how mixed selectivity and other properties evolve with training.

neuroscience↗

bioRxiv2017

Gamma and beta bursts during working memory read-out suggest roles in its volitional control

Working memory (WM) activity is not as stationary or sustained as previously thought. There are brief bursts of gamma ([~]55-120 Hz) and beta ([~]20-35 Hz) oscillations, the former linked to stimulus information in spiking. We examine these dynamics in relation to read-out from WM, which is still not well understood. Monkeys held a sequence of two objects and had to decide if they matched a subsequent sequence. Changes in the balance of beta/gamma suggested their role in WM control. In anticipation of having to use an object for the match decision, there was an increase in spiking information about that object along with an increase in gamma and a decrease in beta. When an object was no longer needed, beta increased and gamma as well as spiking information about that object decreased. Deviations from these dynamics predicted behavioral errors. Thus, turning up or down beta could regulate gamma and the information in working memory.

neuroscience↗