Biology subjects

Manahan-Vaughan, D.

Publications and source records attributed to Manahan-Vaughan, D..

11 recordsLinked to original sources

bioRxiv2026

Strain- and age-dependent divergence in mouse appetitive spatial learning and decision strategies

Animals rely on associative spatial memory to navigate toward previously learned, reward-associated goals. This reward-guided navigation is supported by the hippocampus and its interactions with cortical and subcortical regions: processes which are vital for integrating sensory cues and forming experience-dependent associations. In adulthood, hippocampal-dependent information processing is shaped by aging, reflecting changes in synaptic plasticity and neuromodulatory support. In parallel, mice with distinct genetic backgrounds show systematic differences in behavior, sensory function, and hippocampal plasticity. How mouse strain and age interact to affect spatial appetitive memories has not been well defined. Here, we trained CBA/CaOlaHsd and C57BL/6 mice in early (2-3 months) or late adulthood (7-8 months), in daily training events, to perform a T-maze task with rewards available at a fixed location and decreasing probability in one maze arm. The task consisted of an initial deterministic phase in which a correct response was always rewarded, followed by a probabilistic phase during which reward omissions became increasingly prevalent. We measured correct choices, as well as latencies across training blocks, and combined trial-by-trial metrics with reinforcement learning modeling to assess decision strategies. We observed that CBA/CaOlaHsd mice displayed lower choice latencies than C57BL/6 mice, reached high performance earlier, and maintained better performance when the reward probability decreased. Age was associated with higher latencies and modulated both performance and decision policies in a strain-dependent manner. Moreover, CBA/CaOlaHsd mice displayed higher learning rates from positive outcomes and adopted strategies consistent with more robust context exploitation under uncertainty. C57BL/6 mice, by contrast, exhibited stronger omission-driven strategy switching. Together, these findings reveal robust strain- and age-dependent differences in trial-by-trial decision policies and spatial learning performance.

neuroscience↗

bioRxiv2025

Place cell activity and behaviour during task acquisition and extinction learning predict renewal outcome

Extinction learning (EL) and the subsequent renewal of learned behaviours are crucial for adaptive responding, yet the underlying neural mechanisms that differentiate successful renewal from its absence remain unclear. Here, we explored the behavioral and neurophysiological basis of spatial appetitive EL, as well as renewal failure and renewal success. We recorded place cell activity from hippocampal area CA1 in male rats that performed a context-dependent spatial appetitive learning task in a T-maze (rewarded context A), followed by EL (unrewarded context B), and subsequent renewal testing (unrewarded context A). Half of the animals exhibited significant renewal ("renewers") and the other half failed to renew ("non-renewers"). Our findings reveal fundamental differences in learning strategies between groups revealed by differences in both spatial behavior and in place cell activity during both initial acquisition and subsequent EL. Specifically, renewers exhibited a context-based EL strategy, whereas non-renewers followed a goal-directed strategy. The spatial distribution of hippocampal place cell activity differed significantly between groups, indicating the hippocampus role in the learning processes. Furthermore, renewers exhibited a greater extent of global remapping of place cells compared to non-renewers, consistent with predictions by our computational modeling. This suggests that global remapping serves as a key neural mechanism underlying effective renewal, allowing for the segregation of distinct memories and preventing the generalization of extinction. Our results highlight how hippocampal place cell dynamics during acquisition and EL predict later behavioral renewal outcomes, providing critical insights into the neural basis of memory updating and contextual control over learned behaviors. Significance StatementThis study reveals that individual differences in associative learning strategies determine the outcome of memory renewal/re-activation. After first learning, and then extinguishing, a spatial learning task in two different contexts, some animals renewed their behavior when returned to the acquisition context ("renewers"), while others did not ("non-renewers"). Intriguingly, hippocampal place cell activity during acquisition and extinction learning predicted the subsequent renewal efficacy in these distinct animal groups. In particular, renewers exhibited more global remapping than non-renewers, a neural mechanism that segregates memories from different contexts and prevents over-generalization of extinction. These findings provide critical insights into how the hippocampus supports context-dependent memory acquisition and updating, providing new insights into the physiological basis of individual differences in behavioral flexibility.

neuroscience↗

bioRxiv2025

β-adrenergic receptors modulate CA1 population coding during cumulative spatial memory formation and updating

Hippocampal neuronal ensembles are likely to support the acquisition, stabilization and updating of spatial experience. Spatial learning is typically cumulative, but little is known about how neuronal ensembles are manifested during this process. Here, we used wide-field Ca2+-imaging to monitor CA1 pyramidal cells during cumulative item-place learning in adult male CBA/CaOlaHsd mice. In control mice, initial learning prompted activity in a population of CA1 neurons, some of which re-appeared during re-exposure to the same item-place configuration 60 min after 1st exposure. Item-place reconfiguration (60 min later) caused a change in population dynamics as reflected by alterations in neuronal recruitment and reactivation patterns. Place cell-like properties, population burst activity, and functional connectivity were consistent with the encoding and updating of item-place memory. To examine the role of noradrenergic neuromodulation on these processes, we pharmacologically antagonized {beta}-adrenergic receptors({beta}-AR) prior to the 1st item-place exposure. This led to reduced cellular recruitment, disrupted ensemble reactivation, reduced spatial tuning, dampened population bursts, and altered functional connectivity within neurons. This was accompanied by impaired spatial learning compared to controls. Our results reveal the population activity of CA1 neurons during item-place learning and show that {beta}-AR support memory function by influencing both neuronal and network-level dynamics.

neuroscience↗

bioRxiv2025

Multiplexed detection of nuclear immediate early gene expression reveals hippocampal neuronal subpopulations that engage in the acquisition and updating of spatial experience

Acquired spatial representations are not static. Each re-exposure to the spatial environment stimulates retrieval of the stored experience followed by information re-encoding, including updating if the environment has changed. It remains unclear if the same neurons are involved in these three events. Here, we used a multiplexed fluorescence in situ hybridization(FISH) approach that detected time-locked nuclear immediate early gene(IEG) expression to identify hippocampal neuronal ensembles that were engaged in the acquisition of a spatial representation, as well as its subsequent stabilization and/or updating. Responses were assessed in distal(dCA1) and proximal CA1(pCA1) of male rats. Homer1a was used to detect neuronal recruitment triggered by novel learning of a holeboard environment(HB). cFos and Arc expression was used to detect ensemble stability and/or expansion, or ensemble remodeling, respectively, that was triggered by animal exposure to the now familiar HB that included novel objects(HBO) 25min after the initial HB exposure. Novel HB exposure resulted in nuclear Homer1a expression in both dCA1 and pCA1. Subsequent HBO triggered significant cFos and Arc expression only in dCA1. IEG co-labelling (Homer1a/cFos, Homer1a/Arc and Homer1a/cFos/Arc) was also only evident in dCA1, reflecting both re-iteration and remodeling of dCA1, but not pCA1 ensembles. In sum, we show that the contiguous acquisition and updating of spatial representations recruits distinct populations of CA1-neurons reflecting ensemble selection and stabilization, as well as ensemble remodeling. Moreover, whereas dCA1 and pCA1 are involved in the acquisition of the original spatial representation, only dCA1 is engaged in representation updating related to changes in spatial content information.

neuroscience↗

bioRxiv2025

Sparse memory ensembles set brain-wide network states to sustain learned associations

The ability to recall spatial memories and adapt behavior to changing conditions is essential for efficient navigation of environments. These processes are thought to rely on sparse populations of neurons, embedded within distributed brain networks. However, how the activity of these neurons impacts large-scale network connectivity to sustain behavior remains poorly understood. To address this, we tagged neurons active during peak performance in an appetitive spatial memory T-maze task in male and female TetTag-hM3Dq transgenic mice and chemogenetically reactivated these ensembles during functional magnetic imaging (fMRI) of brain activity. Reactivation of these ensembles triggered widespread network reorganization, optimizing the brain's modular specialization while maintaining integration across the network via key hubs and gateways. We identified two distinct clusters dominated by the ventral and dorsal hippocampus, respectively, that exhibit distinct connectivity with cortical and subcortical areas. Control mice showed effective extinction learning (EL) in the T-maze when the reward incentive was absent. Reactivating the tagged memory ensembles during EL significantly prevented this process. These findings reveal the brain-wide network hubs that support effective spatial memory acquisition, but also indicate that decay of this network connectivity is likely to be an essential facet of effective EL of spatial experience.

neuroscience↗

bioRxiv2024

The suprapyramidal and infrapyramidal blades of the dentate gyrus exhibit different GluN subunit content and dissimilar frequency-dependent synaptic plasticity in vivo

The entorhinal cortex sends afferent information to the hippocampus by means of the perforant path(PP), whereby the medial PP (MPP) is believed to convey information about spatial context and the lateral PP (LPP) may convey information about item identity. This information is encoded by means of synaptic plasticity. The PP input to the dentate gyrus(DG) terminates in the suprapyramidal (upper/inner) and infrapyramidal (lower/outer) blades. To what extent frequency-dependent synaptic plasticity in these blades differs is unclear. Here, we compared MPP-DG responses in the supra- (sDG) and infrapyramidal blades (iDG) of freely behaving adult rats and found that synaptic plasticity in the sDG is broadly frequency-dependent whereby long-term depression (LTD, >24h) is induced with stimulation at 1Hz, short-term depression (<2h) is triggered by 5 or 10Hz and long-term potentiation (LTP) of increasing magnitudes is induced by 200 and 400 Hz stimulation, respectively. By contrast, although the iDG expresses STD following 5 or 10Hz stimulation, LTD induced by 1Hz is weaker, LTP is not induced by 200Hz and LTP induced by 400Hz stimulation is significantly smaller in magnitude and is less persistent (<4h) compared to LTP in sDG. Furthermore, the stimulus-response relationship of the iDG is suppressed compared to sDG. Patch clamp recordings, in vitro, revealed reduced firing frequencies in response to high currents, and different action potential thresholds in iDG compared to sDG. Assessment of the expression of GluN subunits revealed significantly lower expression levels of GluN1, GluN2A and GluN2B in iDG compared to sDG. Taken together, these data indicate that synaptic plasticity in the infrapyramidal blade of the dentate gyrus is weaker, less persistent and less responsive to afferent frequencies than synaptic plasticity in sDG. Effects may be mediated by weaker NMDA receptor expression in iDG. These characteristics may explain reported differences in experience-dependent information processing in sDG versus iDG.

neuroscience↗

bioRxiv2023

Audiovisual stimuli enhance narrowband gamma activity along the mouse thalamocortical visual circuit

To what extent thalamic activity can contribute to multisensory integration at cortical level is unclear. To explore this aspect, we used the mouse narrowband gamma oscillations (NBG), which arise from the lateral geniculate nucleus (LGN) and from upstream retinal inputs, as a tool to investigate potential thalamic audiovisual information transfer to the primary visual cortex (V1). We found that simultaneous bimodal audiovisual stimulation increased the power of V1 NBG. Pharmacological and optogenetic manipulations demonstrated that V1 NBG audiovisual responses occurred independently of primary auditory cortex activation. LGN recordings revealed that the majority of its neurons exhibited audiovisual properties. These properties comprised an increase of both the visual-evoked response and gamma-rhythmicity, indicating that the modulation of V1 NBG by audiovisual stimuli likely has a thalamic origin. Our results reveal a previously unreported subcortical source of audiovisual information transfer in V1 and suggest a new role for the LGN as a multisensory integration and relay center.

neuroscience↗

bioRxiv2021

Why do hippocampal mossy cells matter? It depends on the frequency and context.

The discrimination of similar episodes and places, and their representation as distinct memories, depend on a process called pattern separation that relies on the circuitry of the hippocampal dentate gyrus (DG). Mossy cells (MCs) are key neurons in the circuitry, but how they influence DG network dynamics, function, and seizure risk has not been fully elucidated. We found the net impact of MCs was inhibitory at physiological frequencies connected with learning and behaviour, and their absence associated with deficits in pattern separation and spatial memory; at higher frequencies, their net impact was excitatory, and their absence protected against seizures. Thus, MCs influence DG outputs in a highly dynamic manner that varies with frequency and context. One-Sentence SummaryHippocampal mossy cells are required for learning and memory; but their absence protects against seizures.

neuroscience↗

bioRxiv2021

Genetic depletion of BDNF impairs both context-dependent and context-independent extinction learning of a spatial appetitive task

Brain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent learning, as well as hippocampus-dependent learning. Extinction learning (EL) comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. Concordantly, the participation of BDNF in hippocampus-dependent memory is experience-dependent. BDNF has been associated with synaptic plasticity needed for acquisition and extinction learning of fear conditioning. However, little is known about its influence on the extinction and renewal of spatial appetitive extinction learning (EL). In this study, in BDNF+/--mice we evaluated to what extent BDNF contributes to spatial appetitive EL in the presence (ABA) or absence (AAA) of a context change. Daily training, to reach acquisition criterion in a T-maze, resulted in a similar outcome in BDNF+/--mice or their wildtype (wt) littermates. EL was delayed in the AAA, and significantly impaired in the ABA-context compared to EL in wt littermates. When renewal was tested in the ABA paradigm we detected a significant response in wt controls, but not in BDNF+/--mice. Taken together, these results support an important role for BDNF in EL in AAA and ABA context, as well as renewal of a spatial appetitive task, processes that relate to information updating and retrieval.

neuroscience↗

bioRxiv2020

Context-dependent extinction learning emerging from raw sensory inputs: A reinforcement learning approach

The context-dependence of extinction learning has been well studied and requires the hippocampus. However, the underlying neural mechanisms are still poorly understood. Using memory-driven reinforcement learning and deep neural networks, we developed a model that learns to navigate autonomously in biologically realistic VR environments based on raw camera inputs alone. Neither is context represented explicitly in our model, nor is context change signaled. We find that memory-intact agents learn distinct context representations, and develop ABA renewal, whereas memory-impaired agents do not. These findings reproduce the behavior of control and hippocampal animals, respectively. We therefore propose that the role of the hippocampus in the context-dependence of extinction learning might stem from its function in episodic-like memory and not in context-representation per se. We conclude that context-dependence can emerge from raw visual inputs.

neuroscience↗

bioRxiv2017

Defective synapse maturation and enhanced synaptic plasticity in Shank2-/- mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic aetiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are employed for a mechanistic understanding of ASDs and the development of therapeutic strategies. In sharp contrast to all studies so far on the function of SHANK proteins, we observe enhanced synaptic plasticity in Shank2-/- mice, under various conditions in vitro and in vivo. Reproducing and extending previous results, we here present a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation (LTP) by describing a synaptic maturation deficit in Shank2-/- mice.

neuroscience↗