Biology subjects

Keinath, A. T.

Publications and source records attributed to Keinath, A. T..

11 recordsLinked to original sources

bioRxiv2026

Rapidly decreasing phasic dopamine responses precede a hedonic switch during satiation of sodium appetite

HighlightsO_LIPhasic dopamine tracks changing physiological need during sodium appetite C_LIO_LIRapid decreases in dopamine precede the loss of appetitive behavioural responses C_LIO_LITransitions occur abruptly within individuals despite gradual group averages C_LIO_LIDopamine responses track cumulative sodium intake during sodium satiation C_LI Phasic dopamine signalling updates the value of stimuli and actions. Most empirical support for this critical process involves manipulation of extrinsic stimuli (e.g., reward magnitude, reward omission). Yet interoceptive signals clearly influence motivated behaviour. Sodium depletion generates a sodium appetite where the value of sodium increases. How the value of sodium is updated during ingestion and as animals satiate their need remains unknown. Here, we administered sodium chloride solutions via intraoral delivery and measured appetitive behaviour and dopamine release in sodium replete and deplete rats. Two different concentrations of sodium chloride were used to modulate the rate of repletion for sodium deplete rats. Appetitive behaviour was evoked by infusions only when rats were deplete, and this behavioural motif faded away during the session only when high concentration infusions were delivered. Phasic dopamine release in the nucleus accumbens had a similar pattern. We identified transition points for both behaviour and dopamine in the subgroup of rats that reached satiation and found that transitions were sharp, with dopamine decreasing just before behaviour. Moreover, transitions occurred only after enough sodium was infused to replace that typically lost upon depletion. These findings demonstrate that mesolimbic dopamine dynamically updates the value of taste stimuli based on interoceptive signals that relay satiation.

neuroscience↗

bioRxiv2025

Change-resistance distinguishes the representational geometries of human spatial memory and mouse CA1 in deformed environments

Prior work has highlighted qualitative similarities between the neural instantiations of cognitive maps in rodents and memory-guided navigation in humans, suggesting a conservation of representational structure across species. Yet evidence of cross-species differences in neural coding continues to mount. Our ability to reconcile these similarities and differences has been inherently limited by the qualitative nature of our cross-species comparisons. To overcome this limitation, here we combine recent technical and theoretical advances to characterize the representational geometry of human spatial memory during a diverse set of environmental deformations and compare this geometry to that of mouse CA1. Across three untethered immersive virtual reality experiments (n > 100 participants per experiment), we find that deformations induce compounding local distortions in human spatial memory. These distortions yield a representational geometry which closely resembles a change-resistant version of that of mouse hippocampal CA1 during analogous deformations. The geometries of mouse CA1 subpopulations with higher firing rates, spatial tuning stability, and spatial tuning specificity all better resembled that of human spatial memory. The precision, but not accuracy, of human spatial memory also modulated cross-species resemblance. The local impact of deformations scaled up when humans navigated a larger environment, preserving representational geometry and cross-species resemblance. Neither geometry nor cross-species resemblance depended on the human visual advantage during retrieval. Together, these results establish a common cross-species resemblance in the representational geometry of mouse CA1 and human spatial memory during environmental deformations, with a notable difference in the resistance to change between these assays.

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bioRxiv2024

Idiosyncratic navigation determines mouse CA1 representational structure in a multicompartment environment

Predictive theories of cognitive mapping propose that these representations encode the predictive relationships among contents as experienced by the navigator. One hallmark of these theories is that representational structure in complex environments can be predicted from the behavioral history of the navigator. Here, we image neural activity in hippocampal CA1 as initially naive mice repeatedly navigate a multicompartment environment to test whether representational structure in this subregion is consistent with these predictions. We find that different mice instantiate different patterns of remapping across identically shaped compartments. Within mouse, compartments with more similar predictive navigational histories on a particular spatiotemporal scale are represented more similarly, accounting for these individual differences. Manipulating navigational options induces reorganization of the CA1 structure which specifically resembles the new predictive navigational structure on this scale. Through computational modeling we show that a combination of predictive encoding and geometrically structured inputs can uniquely account for this pattern of results. Together, these results demonstrate that the structure of CA1 representations in complex environments can be predicted from the behavioral history of the navigator, consistent with predictive theories of cognitive mapping.

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bioRxiv2024

Dopamine activity encodes the changing valence of the same stimulus in conditioned taste aversion paradigms

Mesolimbic dopamine encoding of non-contingent rewards and reward-predictive cues has been well established. Considerable debate remains over how mesolimbic dopamine responds to aversion and in the context of aversive conditioning. Inconsistencies may arise from the use of aversive stimuli that are transduced along different neural paths relative to reward or the conflation of responses to avoidance and aversion. Here, we made intraoral infusions of sucrose and measured how dopamine and behavioral responses varied to the changing valence of sucrose. Pairing intraoral sucrose with malaise via injection of lithium chloride (LiCl) caused the development of a conditioned taste aversion (CTA), which rendered the typically rewarding taste of sucrose aversive upon subsequent re-exposure. Following CTA formation, intraoral sucrose suppressed the activity of ventral tegmental area dopamine neurons (VTADA) and nucleus accumbens (NAc) dopamine release. This pattern of dopamine signaling after CTA is similar to intraoral infusions of innately aversive quinine and contrasts with that to sucrose when it was novel or not paired with LiCl. Dopamine responses were negatively correlated with behavioral reactivity to intraoral sucrose and predicted home cage sucrose preference. Further, dopamine responses scaled with the strength of the CTA, which was increased by repeated LiCl pairings and weakened through extinction. Thus, the findings demonstrate differential dopamine encoding of the same taste stimulus according to its valence, which is aligned to distinct behavioral responses.

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bioRxiv2023

Identifying representational structure in CA1 to benchmark theoretical models of cognitive mapping

Decades of theoretical and empirical work have suggested the hippocampus instantiates some form of a cognitive map. Yet, tests of competing theories have been limited in scope and largely qualitative in nature. Here, we develop a novel framework to benchmark model predictions against observed neuronal population dynamics as animals navigate a series of geometrically distinct environments. In this task space, we show a representational structure in the dynamics of hippocampal remapping that generalizes across brains, discriminates between competing theoretical models, and effectively constrains biologically viable model parameters. With this approach, we find that accurate models capture the correspondence in spatial coding of a changing environment. The present dataset and framework thus serve to empirically evaluate and advance theories of cognitive mapping in the brain. HIGHLIGHTSO_LIWe identify representational structure in CA1 remapping that is reliable across brains. C_LIO_LIWe directly compare models of cognitive mapping to this representation in CA1. C_LIO_LIModels based on local boundary distance and direction predict CA1 representation. C_LIO_LIThis approach reveals a biologically viable parameter space for model predictions. C_LIO_LIAccurate models capture the correspondence of spatial codes across environments. C_LI

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bioRxiv2023

Representational similarity supports rapid context retrieval during fear discrimination in ventral hippocampus

The dorsal and ventral regions of the hippocampus (dCA1 and vCA1) are critical for contextual fear conditioning tasks, yet the dynamics of hippocampal neuronal representations during memory acquisition, retrieval, and extinction processes have yet to be fully elucidated. The canonical theory is that the hippocampus generates and retrieves spatial maps of contexts during memory acquisition and retrieval. It is hypothesized the hippocampus prevents memory interference by generating context representations that are dissimilar and the prediction follows that representation dissimilarity facilitates discrimination between contexts. Here, we developed a context fear memory retrieval task and combined it with 1-photon neuronal imaging in dCA1 and vCA1 of freely behaving mice to test this prediction. We identified several phenomena specific to vCA1. First, fear conditioning induced an immediate and strong representational change that was predictive of freezing behavior. During context discrimination, vCA1 representations of the threatening and neutral contexts became more similar. Third, during threatening context memory retrieval, vCA1 expressed rapid and strong context representations. These unexpected results suggest that representational similarity in vCA1 facilitates faster and more efficient network state transitions. In further support of this view, both phenomena of representational similarity and rapid context recall were no longer observed in vCA1 once fear behavior was extinguished. Together, these results reveal that vCA1 unexpectedly generates similar population codes, promoting faster transitions between network states essential for contextual fear memory retrieval. HighlightsO_LIWe established a novel context teleportation task that allows population level hippocampal recordings during key moments of threat memory acquisition, retrieval, and extinction. C_LIO_LIThe ventral region of CA1 (vCA1) exhibited the greatest change in neural representation during fear memory acquisition, compared to dorsal CA1 (dCA1). C_LIO_LIAfter fear conditioning, representations for threatening and neutral contexts were more similar in vCA1 compared to dCA1, yet representational similarity in vCA1 supported rapid context memory retrieval. C_LIO_LIContext fear memory extinction reversed the context representation in vCA1 to patterns observed prior to fear conditioning. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/556889v1_ufig1.gif" ALT="Figure 1"> View larger version (104K): org.highwire.dtl.DTLVardef@1dd5ba2org.highwire.dtl.DTLVardef@1ab16c5org.highwire.dtl.DTLVardef@1640a6dorg.highwire.dtl.DTLVardef@e87cde_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2021

Population dynamics of the thalamic head direction system during drift and reorientation

The head direction (HD) system is classically modeled as a ring attractor network1,2 which ensures a stable representation of the animals head direction. This unidimensional description popularized the view of the HD system as the brains internal compass3,4. However, unlike a globally consistent magnetic compass, the orientation of the HD system is dynamic, depends on local cues and exhibits remapping across familiar environments5. Such a system requires mechanisms to remember and align to familiar landmarks, which may not be well described within the classic 1-dimensional framework. To search for these mechanisms, we performed large population recordings of mouse thalamic HD cells using calcium imaging, during controlled manipulations of a visual landmark in a familiar environment. First, we find that realignment of the system was associated with a continuous rotation of the HD network representation. The speed and angular distance of this rotation was predicted by a 2nd dimension to the ring attractor which we refer to as network gain, i.e. the instantaneous population firing rate. Moreover, the 360-degree azimuthal profile of network gain, during darkness, maintained a memory trace of a previously displayed visual landmark. In a 2nd experiment, brief presentations of a rotated landmark revealed an attraction of the network back to its initial orientation, suggesting a time-dependent mechanism underlying the formation of these network gain memory traces. Finally, in a 3rd experiment, continuous rotation of a visual landmark induced a similar rotation of the HD representation which persisted following removal of the landmark, demonstrating that HD network orientation is subject to experience-dependent recalibration. Together, these results provide new mechanistic insights into how the neural compass flexibly adapts to environmental cues to maintain a reliable representation of the head direction.

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bioRxiv2021

Disruption of the grid cell network in a mouse model of early Alzheimer's disease

Early-onset familial Alzheimers disease (AD) is marked by an aggressive buildup of amyloid beta (A{beta}) proteins, yet the neural circuit operations impacted during the initial stages of A{beta} pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in a transgenic mouse model of familial AD that over-expresses A{beta} throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of A{beta} fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread A{beta}-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.

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bioRxiv2021

Extended experience reveals distinct representational dynamics governing the CA1 spatial code

The hippocampus is thought to mediate episodic memory through the instantiation and reinstatement of context-specific cognitive maps. However, recent longitudinal experiments have challenged this view, reporting that most hippocampal cells change their tuning properties over days even in the same environment. Often referred to as representational drift, these dynamics raise multiple questions about the representational capacity and content of the hippocampal code. One such question is whether and how these dynamics impact the contextual code. To address this, here we imaged large CA1 populations over more than a month of daily experience as freely behaving mice participated in an extended geometric morph paradigm. We find that long-timescale changes in population activity occurred orthogonally to the representation of context in network space, allowing for consistent readout of contextual information across weeks. Together, these results demonstrate that long-timescale changes to the CA1 spatial code preserve the relative structure of contextual representation.

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bioRxiv2019

DG-CA3 circuitry mediates hippocampal representations of latent information

Survival in complex environments necessitates a flexible navigation system that incorporates memory of recent behavior and associations. Yet, how the hippocampal spatial circuit represents latent information independent of sensory inputs and future goals has not been determined. To address this, we imaged the activity of large ensembles in subregion CA1 via wide-field fluorescent microscopy during a novel behavioral paradigm. Our results demonstrated that latent information is represented through reliable firing rate changes during unconstrained navigation. We then hypothesized that the representation of latent information in CA1 is mediated by pattern separation/completion processes instantiated upstream within the dentate gyrus (DG) and CA3 subregions. Indeed, CA3 ensemble recordings revealed an analogous code for latent information. Moreover, selective chemogenetic inactivation of DG-CA3 circuitry completely and reversibly abolished the CA1 representation of latent information. These results reveal a causal and specific role of DG-CA3 circuitry in the maintenance of latent information within the hippocampus.

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bioRxiv2017

Environmental deformations dynamically shift the spatial metric of the brain

Environmental deformations induce stereotyped distortions in the time-averaged activity of grid and place cells. We hypothesized that these effects are partly driven by border cell inputs which reset the spatial phase of grid cells, maintaining learned relationships between grid phase and environmental boundaries without altering inherent grid scale. A computational model of this mechanism reproduced diverse distortions during deformations, including scale-dependent and local distortions of grid fields, and stretched, duplicated, and fractured place fields. This model predicted a striking new effect: dynamic, history-dependent, boundary-tethered shifts in grid phase during deformations. We reanalyzed two rodent grid cell rescaling datasets and found direct evidence of these shifts, which have not been previously reported and contribute to the appearance of rescaling. These results demonstrate that the grid representation of geometrically deformed environments is not fixed, but rather dynamically changes with the specific experience of the navigator.

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