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Sah, P.

Publications and source records attributed to Sah, P..

9 recordsLinked to original sources

Distinct prefrontal-amygdala connectivity drives consolidated fear memories

Elucidating the neuronal circuitry that underpins memory formation is critical to understanding how organisms use past experience to guide adaptive behaviour. While memory formation has long been framed as the reactivation of a static ensemble of neurons established during initial learning, growing evidence suggests that memory traces are highly dynamic and undergo substantial reorganisation during consolidation. During the formation of auditory fear memory, initial acquisition is primarily mediated by the basolateral amygdala (BLA), whereas long-term expression relies on the medial prefrontal cortex (mPFC). However, the circuit motifs that coordinate this systemic redistribution remain poorly understood. Here, using targeted anatomical tracing and electrophysiology, we show that the reciprocal connectivity between the mPFC and BLA is organised as a parallel topography along the rostro-caudal axis. Leveraging this novel anatomical understanding of reciprocal communication between the amygdala and prefrontal cortex, we reveal an underlying circuitry mechanism by which fear memory traces are redistributed into subcortical-cortical networks after learning. Using activity-dependent engram capture and optogenetic manipulation, we demonstrate that post-learning engagement of a distinct sub-circuit linking the rostral BLA and rostral mPFC is a hallmark of the consolidated fear memory. These insights reveal that the consolidated engram requires the targeted engagement of a post-learning engram circuit, rather than a simple reactivation of neurons engaged during initial learning.

neuroscience↗

Modulation of pedunculopontine input to the basal ganglia relieves motor symptoms in Parkinsonian mice

Locomotion, the ability to move, is driven by central pattern generators in the spinal cord. However, its initiation, selection of gait and arrest are controlled by command centers in the brain stem of which the best understood is the mesencephalic locomotor region (MLR). Stimulation of the MLR can initiate or arrest movement, but its neural projections and the neural circuits that mediate these actions are poorly understood. Here we show that glutamatergic neurons in the pedunculopontine nucleus (PPN), a major part of the MLR, project to the substantial nigra pars reticulata (SNr) where they innervate neurons that send afferents to the ventro medial motor thalamus (VM). Stimulation of this input to the SNr in mice slows voluntary and driven movement by modifying gait, with higher frequencies arresting gait. In Parkinsons disease (PD), a neurodegenerative disorder, the cardinal symptoms are bradykinesia, tremor and rigidity. Using an mouse model of PD, we show that inhibition of PPN input to the SNr rescues bradykinesia. This is the first description of a circuit in the mammalian brain that regulates movement and gait selection. Targeting of this circuit may be a more effective modality for treating the motor symptoms of PD.

neuroscience↗

Recognition of Chlamydia trachomatis by Toll-Like Receptor 9 is altered during persistence.

Toll-like receptor 9 (TLR9) is an innate immune receptor that localizes to endosomes in antigen presenting cells and recognizes single stranded unmethylated CpG sites on bacterial genomic DNA. Previous bioinformatic studies have indicated that the genome of the human pathogen Chlamydia trachomatis contains TLR9 stimulatory motifs, and correlative studies have implied a link between human TLR9 (hTLR9) genotype variants and susceptibility to infection. Here we present our evaluation of the stimulatory potential of C. trachomatis gDNA and its recognition by hTLR9- and murine TLR9 (mTLR9)-expressing cells. We confirm that hTLR9 colocalizes with chlamydial inclusions in the pro-monocytic cell line, U937. Utilizing HEK293 reporter cell lines, we demonstrate that purified genomic DNA from C. trachomatis can stimulate hTLR9 signaling, albeit at lower levels than gDNA prepared from other Gram-negative bacteria. Interestingly, we found that while C. trachomatis is capable of signaling through hTLR9 and mTLR9 during live infections in non-phagocytic HEK293 reporter cell lines, signaling only occurs at later developmental time points. Chlamydia-specific induction of hTLR9 is blocked when protein synthesis is inhibited prior to the RB-to-EB conversion and exacerbated by the inhibition of lipooligosaccharide biosynthesis. The induction of aberrance / persistence also significantly alters Chlamydia-specific TLR9 signaling. Our observations support the hypothesis that chlamydial gDNA is released at appreciable levels by the bacterium during the conversion between its replicative and infectious forms and during treatment with antibiotics targeting peptidoglycan assembly.

microbiology↗

Resting-state network hubs are causally required in memory consolidation

Memory consolidation after learning involves spontaneous, brain-wide network reorganization during rest and sleep, but how this is achieved is still poorly understood. Current theory suggests that the hippocampus is pivotal for reshaping the connectivity. Here we identify that a different set of spontaneous networks and their hubs are instrumental in consolidating memory during post-learning rest. We found that two types of spatial memory training invoke distinct functional connections, but a network of the sensory cortex and subcortical areas is common for both tasks. Furthermore, learning increased brain-wide network integration, with the prefrontal, striatal and thalamic areas being influential for this network-level reconfiguration. Chemogenetic suppression of each hub identified after learning resulted in retrograde amnesia, confirming the behavioral significance. These results demonstrate the causal and functional roles of resting-state network hubs in memory consolidation and suggest a distributed network beyond the hippocampus subserving this process.

animal behavior and cognition↗

A midbrain - thalamus - cortex circuit reorganizes cortical dynamics to initiate planned movement

Motor behaviors are often planned long before execution, but only released after specific sensory events. Planning and execution are each associated with distinct patterns of motor cortex activity. Key questions are how these dynamic activity patterns are generated and how they relate to behavior. Here we investigate the multi-regional neural circuits that link an auditory go cue and the transition from planning to execution of directional licking. Ascending glutamatergic neurons in the midbrain reticular and pedunculopontine nuclei show short-latency and phasic changes in spike rate that are selective for the go cue. This signal is transmitted via the thalamus to the motor cortex, where it triggers a rapid reorganization of motor cortex state from planning-related activity to a motor command, which in turn drives appropriate movement. Our studies show how brainstem structures can control cortical dynamics via the thalamus for rapid and precise motor behavior.

neuroscience↗

Hippocampal-amygdala interactions mediate uncertainty-dependent resistance to extinction following fear conditioning

The partial reinforcement extinction effect (PREE) is a paradoxical learning phenomenon in which omission of reinforcement during acquisition results in more persistent conditioned responding in extinction. Here, we report a significant PREE with an inverted-U, entropy-like distribution against reinforcement probability following tone foot shock fear conditioning in rats, which was associated with increased neural activity in hippocampus and amygdala as indexed by p-ERK and c-fos immunolabelling. In vivo electrophysiological recordings of local field potentials (LFPs) showed that 50% reinforcement was associated with increases in the frequency and power of tone-evoked theta oscillations in both the subiculum region of hippocampus and in basolateral amygdala (BLA) during both acquisition (Day 1) and extinction (Day 2) sessions. Tone-evoked LFPs in 50% reinforced animals also showed increases in coherence and bidirectional Granger Causality between hippocampus and amygdala. The results support a Bayesian interpretation of the PREE, in which the phenomenon is driven by increases in the entropy or uncertainty of stimulus contingencies, and indicate a crucial role for hippocampus in mediating this uncertainty-dependent effect.

neuroscience↗

A multi-species repository of social networks

Social network analysis is an invaluable tool to understand the patterns, evolution, and consequences of sociality. Comparative studies over the spectrum of sociality across taxonomic groups are particularly valuable. Such studies however require quantitative information on social interactions across multiple species which is not easily available. We introduce the Animal Social Network Repository (ASNR) as the first multi-taxonomic repository that collates more than 650 social networks from 47 species, including those of mammals, reptiles, fish, birds, and insects. The repository was created by consolidating social network datasets from the literature on wild and captive animals into a consistent and easy-to-use network data format. The repository is archived at https://bansallab.github.io/asnr/. ASNR has tremendous research potential, including testing hypotheses in the fields of animal ecology, social behavior, epidemiology and evolutionary biology.

animal behavior and cognition↗

Identifying the dynamic contact network of infectious disease spread

The spread of pathogens fundamentally depends on the underlying contacts between individuals. Modeling infectious disease dynamics through contact networks is sometimes challenging, however, due to a limited understanding of pathogen transmission routes and infectivity. We developed a novel tool, INoDS (Identifying Network models of infectious Disease Spread) that estimates the predictive power of empirical contact networks to explain observed patterns of infectious disease spread. We show that our method is robust to partially sampled contact networks, incomplete disease information, and enables hypothesis testing on transmission mechanisms. We demonstrate the applicability of our method in two host-pathogen systems: Crithidia bombi in bumble bee colonies and Salmonella in wild Australian sleepy lizard populations. The performance of INoDS in synthetic and complex empirical systems highlights its role in identifying transmission pathways of novel or neglected pathogens, as an alternative approach to laboratory transmission experiments, and overcoming common data-collection constraints.

epidemiology↗

Disease implications of animal social organization and network structure - a quantitative analysis

O_LIThe disease costs of sociality have largely been understood through the link between group size and transmission. However, infectious disease spread is driven primarily by the social organization of interactions in a group and not its size.\nC_LIO_LIWe used statistical models to review the social network organization of 47 species, including mammals, birds, reptiles, fish and insects by categorizing each species into one of three social systems, relatively solitary, gregarious and socially hierarchical. Additionally, using computational experiments of infection spread, we determined the disease costs of each social system.\nC_LIO_LIWe find that relatively solitary species have large variation in number of social partners, that socially hierarchical species are the least clustered in their interactions, and that social networks of gregarious species tend to be the most fragmented. However, these structural differences are primarily driven by weak connections, which suggests that different social systems have evolved unique strategies to organize weak ties.\nC_LIO_LIOur synthetic disease experiments reveal that social network organization can mitigate the disease costs of group living for socially hierarchical species when the pathogen is highly transmissible. In contrast, highly transmissible pathogens cause frequent and prolonged epidemic outbreaks in gregarious species.\nC_LIO_LIWe evaluate the implications of network organization across social systems despite methodological challenges, and our findings offer new perspective on the debate about the disease costs of group living. Additionally, our study demonstrates the potential of meta-analytic methods in social network analysis to test ecological and evolutionary hypotheses on cooperation, group living, communication, and resilience to extrinsic pressures.\nC_LI

epidemiology↗