Biology subjects

Zaki, Y.

Publications and source records attributed to Zaki, Y..

11 recordsLinked to original sources

bioRxiv2026

State-dependent geometric transformations in the mouse hippocampus support fear generalization without loss of discriminability

Learning from aversive experiences often generalizes beyond the context in which they occurred. In rodents, a strong aversive event can induce retrospective memory linking (RLI), whereby fear generalizes to a previously neutral context encountered days earlier. Although prior work has shown that RLI is associated with increased co-activity of hippocampal CA1 neurons across neutral and aversive contexts, it remains unclear how broader representational changes support generalization without affecting the ability to discriminate between contexts. Here, we reanalyzed calcium imaging data from dorsal CA1 during RLI to examine how hippocampal representational geometry changes during fear generalization. Using robust, non-parametric measures of population similarity, we show that in mice exhibiting RLI, the representation of the neutral context not only changes over time but becomes more similar to the aversive context during recall. Beyond this similarity increase, we provide evidence for a higher-dimensional geometric transformation consistent with a shared "fear" operation that can be applied across contexts while preserving their identity. Crucially, these two representational signatures dissociate by behavioral state: similarity to the aversive context emerges during freezing, whereas a shared transformation is expressed during active exploration. Together, these findings demonstrate that hippocampal representations support retrospective fear generalization through state-dependent geometric transformations, highlighting representational geometry as a key computational mechanism to resolve the apparent tension between generalization and discriminability.

neuroscience↗

bioRxiv2024

Chemotagging: a chemogenetic approach for identifying cell types with in vivo calcium imaging

The ability to monitor the activity of specific cell types in vivo is critical for understanding the complex interplay between various neuronal populations driving freely moving behavior. Existing methods, such as optogenetic tagging (i.e., Optotagging1), have proven useful for identifying cell types in in vivo electrophysiological recordings during freely moving behavior. However, electrophysiological recordings are limited in their capacity to track the same neuronal populations across long periods of time (days to weeks). Single-photon miniscope imaging offers the advantage of tracking the same cells across weeks to months; however, it is difficult to distinguish different cell types within the recorded population. Here, we present "chemotagging," a technique that allows for the identification of specific cell types in in vivo calcium imaging recordings. This protocol offers a method for tagging cell types with chemogenetic tools like Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)2, while simultaneously recording calcium activity from a pan-neuronal population with calcium indicators. We highlight the key advantages and limitations of chemotagging and its potential implications for neuroscience research.

neuroscience↗

bioRxiv2024

An anterior hypothalamic circuit gates stress vulnerability

Prior adversity increases susceptibility to subsequent stressful events, but the causal underlying changes in brain circuitry are poorly understood. We harnessed unbiased whole-brain activity mapping to identify circuits that are functionally remodeled by prior adversity. This revealed that the anterior hypothalamic nucleus (AHN) displays heightened stress reactivity in previously stressed mice. This was accompanied by increased functional connectivity between the AHN and a threat-related limbic network. Using in vivo Miniscope imaging, we found that neuronal activity in the AHN encodes stressor valence. Moreover, stimulating AHN neurons enhanced, and inhibiting their activity mitigated, reactivity to stressful events. Lastly, silencing amygdala inputs to the AHN abolished the ability of prior adversity to increase stress sensitivity. These findings define a key role of the AHN in gating stress vulnerability by scaling valence signals from the amygdala.

neuroscience↗

bioRxiv2024

Simultaneous dual-color calcium imaging in freely-behaving mice

Miniaturized fluorescence microscopes (miniscopes) enable imaging of calcium events from a large population of neurons in freely behaving animals. Traditionally, miniscopes have only been able to record from a single fluorescence wavelength. Here, we present a new open-source dual-channel Miniscope that simultaneously records two wavelengths in freely behaving animals. To enable simultaneous acquisition of two fluorescent wavelengths, we incorporated two CMOS sensors into a single Miniscope. To validate our dual-channel Miniscope, we imaged hippocampal CA1 region that co-expressed a dynamic calcium indicator (GCaMP) and a static nuclear signal (tdTomato) while mice ran on a linear track. Our results suggest that, even when neurons were registered across days using tdTomato signals, hippocampal spatial coding changes over time. In conclusion, our novel dual-channel Miniscope enables imaging of two fluorescence wavelengths with minimal crosstalk between the two channels, opening the doors to a multitude of new experimental possibilities. TeaserNovel open-source dual-channel Miniscope that simultaneously records two wavelengths with minimal crosstalk in freely behaving animals.

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bioRxiv2023

Drift of neural ensembles driven by slow fluctuations of intrinsic excitability

Representational drift refers to the dynamic nature of neural representations in the brain despite the behavior being seemingly stable. Although drift has been observed in many different brain regions, the mechanisms underlying it are not known. Since intrinsic neural excitability is suggested to play a key role in regulating memory allocation, fluctuations of excitability could bias the reactivation of previously stored memory ensembles and therefore act as a motor for drift. Here, we propose a rate-based plastic recurrent neural network with slow fluctuations of intrinsic excitability. We first show that subsequent reactivations of a neural ensemble can lead to drift of this ensemble. The model predicts that drift is induced by co-activation of previously active neurons along with neurons with high excitability which leads to remodeling of the recurrent weights. Consistent with previous experimental works, the drifting ensemble is informative about its temporal history. Crucially, we show that the gradual nature of the drift is necessary for decoding temporal information from the activity of the ensemble. Finally, we show that the memory is preserved and can be decoded by an output neuron having plastic synapses with the main region.

neuroscience↗

bioRxiv2023

Aversive experience drives offline ensemble reactivation to link memories across days

Memories are encoded in neural ensembles during learning and stabilized by post-learning reactivation. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how the brain accomplishes this critical process remains unknown. Here we show that in mice, a strong aversive experience drives the offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed two days prior, linking the fear from the recent aversive memory to the previous neutral memory. We find that fear specifically links retrospectively, but not prospectively, to neutral memories across days. Consistent with prior studies, we find reactivation of the recent aversive memory ensemble during the offline period following learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Finally, the expression of fear in the neutral context is associated with reactivation of the shared ensemble between the aversive and neutral memories. Taken together, these results demonstrate that strong aversive experience can drive retrospective memory-linking through the offline co-reactivation of recent memory ensembles with memory ensembles formed days prior, providing a neural mechanism by which memories can be integrated across days.

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bioRxiv2023

Development of prefrontal corticostriatal connectivity in mice

Rational decision making is grounded in learning to associate actions with outcomes, a process that depends on projections from prefrontal cortex to dorsomedial striatum. Symptoms associated with a variety of human pathological conditions ranging from schizophrenia and autism to Huntingtons and Parkinsons disease point toward functional deficits in this projection, but its development is not well understood, making it difficult to investigate how perturbations in development of this circuitry could contribute to pathophysiology. We applied a novel strategy based on Hotspot Analysis to assess the developmental progression of anatomical positioning of prefrontal cortex to striatal projections. Corticostriatal axonal territories established at P7 expand in concert with striatal growth but remain largely unchanged in positioning through adulthood, indicating they are generated by directed, targeted growth and not modified extensively by postnatal experience. Consistent with these findings, corticostriatal synaptogenesis increased steadily from P7 to P56, with no evidence for widescale pruning. As corticostriatal synapse density increased over late postnatal ages, the strength of evoked PFC input onto dorsomedial striatal projection neurons also increased, but spontaneous glutamatergic synaptic activity was stable. Based on its pattern of expression, we asked whether the adhesion protein, Cdh8, influenced this progression. In mice lacking Cdh8 in PFC corticostriatal projection neurons, axon terminal fields in dorsal striatum shifted ventrally. Corticostriatal synaptogenesis was unimpeded, but spontaneous EPSC frequency declined and mice failed to learn to associate an action with an outcome. Collectively these findings show that corticostriatal axons grow to their target zone and are restrained from an early age, do not undergo postnatal synapse pruning as the most dominant models predict, and that a relatively modest shift in terminal arbor positioning and synapse function has an outsized, negative impact on corticostriatal-dependent behavior.

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bioRxiv2021

Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system in mice, we label dorsal dentate gyrus neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells are artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory is sufficient to update the memory during reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrate operant responding for reactivation of a positive memory, confirming its rewarding properties. These results show that interference from a rewarding experience can counteract negative affective states. While memory-updating, induced by memory reactivation, involves a relatively small set of neurons, we also find that activating a large population of randomly labeled dorsal dentate gyrus neurons is effective in promoting reconsolidation. Importantly, memory-updating is specific to the fear memory. These findings implicate the dorsal dentate gyrus as a potential therapeutic node for modulating memories to suppress fear.

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bioRxiv2021

Minian: An open-source miniscope analysis pipeline

Miniature microscopes have gained considerable traction for in vivo calcium imaging in freely behaving animals. However, extracting calcium signals from raw videos is a computationally complex problem and remains a bottleneck for many researchers utilizing single-photon in vivo calcium imaging. Despite the existence of many powerful analysis packages designed to detect and extract calcium dynamics, most have either key parameters that are hard-coded or insufficient step-by-step guidance and validations to help the users choose the best parameters. This makes it difficult to know whether the output is reliable and meets the assumptions necessary for proper analysis. Moreover, large memory demand is often a constraint for setting up these pipelines since it limits the choice of hardware to specialized computers. Given these difficulties, there is a need for a low memory demand, user-friendly tool offering interactive visualizations of how altering parameters at each step of the analysis affects data output. Our open-source analysis pipeline, Minian (Miniscope Analysis), facilitates the transparency and accessibility of single-photon calcium imaging analysis, permitting users with little computational experience to extract the location of cells and their corresponding calcium traces and deconvolved neural activities. Minian contains interactive visualization tools for every step of the analysis, as well as detailed documentation and tips on parameter exploration. Furthermore, Minian has relatively small memory demands and can be run on a laptop, making it available to labs that do not have access to specialized computational hardware. Minian has been validated to reliably and robustly extract calcium events across different brain regions and from different cell types. In practice, Minian provides an open-source calcium imaging analysis pipeline with user-friendly interactive visualizations to explore parameters and validate results.

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bioRxiv2021

Social Reactivation of Fear Engrams Enhances Recall and Reinstatement

For group-living species such as humans and rodents, conspecific interactions pervasively shape emotion (1-3), attention (4), and cognitive ability (5-8). Higher-order cognitive processes such as memory within a social brain are thus interlaced with social influences. Traditional laboratory rodent cages offer a limited but nonetheless rich multi-modal landscape of communication, including auditory calls (9-12), chemical signaling (13, 14), and tactile stimulation (15, 16). The absence of such social encounters in singly housed animals results in cognitive impairments and depression-like phenotypes (17), likely obscuring how the social brain has evolved to function. It is thus important to understand the relationship between social context and how individuals process memories. As social interaction recruits hippocampal (18) and amygdalar (19) circuitry that also serves as hubs for non-social memory traces(20-24), we hypothesized that pre-existing ensembles in these regions can be modulated by social experiences and lead to changes in memory expression. Here we show that stressful social experiences enhance the recall of previously acquired fear memories in male but not female mice. Activity-dependent tagging of cells in the dentate gyrus (DG) during fear learning revealed that these ensembles were endogenously reactivated during the social experiences in males. These reactivated cells were shown to be functional components of engrams, as optogenetic stimulation of the cells active during the social experience in previously fear conditioned animals was sufficient to drive fear-related behaviors. Our findings suggest that social encounters can reactivate pre-existing DG engrams and thereby strengthen discrete memories. Significance StatementSocial environments can bolster and protect cognitive abilities. However, the relationship between social stimuli and individually learned memories remains enigmatic. Our work reveals that exposure to a stressed, naive non-familiar conspecific or to the ambient olfactory-auditory cues of a recently stressed familiar conspecific induces reactivation of the cellular ensembles associated with a fear memory in the hippocampus. Artificially activating the hippocampal ensemble active during the social experience induces fearful behaviors only in animals that have previously acquired a negative memory, suggesting a fear-driving function of the reactivated ensembles and demonstrating the interaction between individual history and social experience. The neural resurgence of fear-driving ensembles during social experiences leads to a context-specific enhancement of fear recall. Our findings provide evidence that unlike directly physical stressors, ambient social stimuli can reactivate and amplify an individuals memories.

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bioRxiv2019

Hippocampus and amygdala fear memory engrams re-emerge after contextual fear reinstatement

The formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in male mice, cells active during fear conditioning in the dentate gyrus of hippocampus exhibit decreased activity during extinction and are re-engaged after contextual fear relapse. In vivo calcium imaging reveals that relapse drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after relapse. These results suggest that fear relapse triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse.

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