Biology subjects

Radulovic, J.

Publications and source records attributed to Radulovic, J..

7 recordsLinked to original sources

bioRxiv2026

Hippocampal CA2 modulates trace fear conditioning through circuit-specific control of CA1

Forming associations between temporally separated events depends on pathways linking the CA1, the subiculum (SUB), and the entorhinal cortex. The degree to which this process requires the CA2, which shares extensive connectivity with these regions, remains unknown. Using trace fear conditioning (TFC), where mice learn to associate a tone and shock separated by a temporal gap, we showed that the dCA2 contributes to TFC. Interestingly, whereas chronic dCA2 inhibition decreased cue-associated freezing, acute dCA2[->]dCA1 projection inhibition increased freezing. Combined with differential effects on cFos expression, this suggests that global and projection-specific perturbations of the dCA2 have distinct effects on TFC and hippocampal activity states. Fiber photometry revealed that dCA2[->]dCA1 activity shifted from tone responsiveness during conditioning to expected shock activation during recall, consistent with learning-associated activity remodeling. Together, these findings identify the dCA2 as a contributor to TFC and implicate dCA2[->]dCA1 signaling in shaping fear expression across learning and recall.

neuroscience↗

bioRxiv2025

Response dynamics of discrete subiculum->retrosplenial cortex projections underlying trace fear conditioning

Associating events separated in time depends on the CA1, subiculum (SUB), and retrosplenial cortex (RSP). The degree to which their connectivity and underlying circuit mechanisms contribute to the association of such temporally discontiguous events is not known. Here we showed, using trace fear conditioning (TFC), wherein mice learn to associate tone and shock separated by a temporal trace, that molecularly distinct excitatory VGluT1+ and VGluT2+ SUB[->]RSP projections subserve the associative and temporal components of TFC. During trace memory formation, VGluT2+ SUB[->]RSP projections showed increased and decreased bulk calcium activity at tone and trace onset, respectively, an activity pattern that was reestablished during memory recall. Such pattern was not observed in CA subfields, suggesting that associative and temporal components of TFC are integrated at the SUB or SUB[->]RSP synapses before being presented to the RSP. Our findings establish a circuit mechanism for representing complex temporal information in episodic memory.

neuroscience↗

bioRxiv2025

NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease

The increasing evidence that non-coding RNAs can become deregulated during pathogenesis is dramatically expanding the space for drug discovery beyond the protein-coding genome. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular function, yet most remain uncharacterized. Here, we identify a previously unstudied lncRNA, which we named Neuronal Identity (NeuID)--a conserved, brain-enriched transcript expressed exclusively in neurons. NeuID is downregulated in the brains of Alzheimers disease (AD) patients. Mechanistically, NeuID maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of NeuID disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated NeuID overexpression restores neuronal function in A{beta}42-treated neurons. These findings identify NeuID as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD. One sentence summaryWe identify NeuID, a novel brain and neuron-specific long non-coding RNA downregulated in Alzheimers disease, as a key regulator of neuronal identity and a promising therapeutic target to restore neuronal function.

neuroscience↗

bioRxiv2025

Cholinergic disruption of state-dependent retrosplenial layer 1 activity causes temporal associative memory deficit under stress

Memory functions rely on discrete patterns of neuronal activity emerging from individual neurons, their interconnected circuits, and their alignment with global brain states. We show that such patterns are generated by layer 1 inhibitory neurons in the ventral retrosplenial cortex (vRSPL1), whose activity correlated with immobility and specifically contributed to the formation of temporal associative memories. This state-dependent activity was subject to stress-induced cholinergic modulation through muscarinic 1 receptor (M1R) signaling, leading to selective impairments in temporal but not contextual associative memory. Slice studies showed that these effects were likely due to M1R-mediated inhibition of vRSPL1 neurons, transiently disrupting their local connectivity as well as responsiveness to afferent input. Together, we demonstrate a mechanism by which vRSPL1 activity aligned to immobility coordinate the formation of temporal associations. Through its sensitivity to stress-related cholinergic modulation, this mechanism presents vulnerability to traumatic amnesia, especially for temporal details of episodic memories.

neuroscience↗

bioRxiv2024

Endopiriform neurons projecting to ventral CA1 are a critical node for recognition memory

The claustrum complex is viewed as fundamental for higher order cognition; however, the circuit organization and function of its neuroanatomical subregions are not well understood. We demonstrated that some of the key roles of the CLA complex can be attributed to the connectivity and function of a small group of neurons in its ventral subregion, the endopiriform (EN). We identified a subpopulation of EN neurons by their projection to the ventral CA1 (ENvCA1-proj. neurons), embedded in recurrent circuits with other EN neurons and the piriform cortex. Although the ENvCA1-proj. neuron activity was biased toward novelty across stimulus categories, their chemogenetic inhibition selectively disrupted the memory-guided but not innate responses of mice to novelty. Based on our functional connectivity analysis, we suggest that ENvCA1-proj. neurons serve as an essential node for recognition memory through recurrent circuits mediating sustained attention to novelty, and through feed forward inhibition of distal vCA1 neurons shifting memory-guided behavior from familiarity to novelty.

neuroscience↗

bioRxiv2018

Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons

Dorsal hippocampus, retrosplenial cortex (RSC), and anterior thalamic nuclei (ATN) interact to mediate diverse cognitive functions, but the cellular basis for these interactions is unclear. We hypothesized a long-range circuit converging in layer 1 (L1) of RSC, based on the pathway anatomy of GABAergic CA1 retrosplenial-projecting (CA1-RP) neurons and thalamo-restrosplenial projections from ATN. We find that CA1[->]RSC projections stem from GABAergic neurons with a distinct morphology, electrophysiology, and molecular profile, likely corresponding to recently described Ntng1-expressing hippocampal interneurons. CA1-RP neurons monosynaptically inhibit L5 pyramidal neurons, principal outputs of RSC, via potent GABAergic synapses onto apical tuft dendrites in L1. These inhibitory inputs align precisely with L1-targeting thalamocortical excitatory inputs from ATN, particularly the anteroventral nucleus, forming a convergent circuit whereby CA1 inhibition can intercept ATN excitation to co-regulate RSC activity. Excitatory axons from subiculum, in contrast, innervate proximal dendrites in deeper layers. Short-term synaptic plasticity differs at each connection. Chemogenetically abrogating inhibitory CA1[->]RSC or excitatory ATN[->]RSC connections oppositely affects the encoding of contextual fear memory. Collectively, our findings identify multiple cellular mechanisms underlying hippocampo-thalamo-retrosplenial interactions, establishing CA1 RSC-projecting neurons as a distinct class with long-range axons that target apical tuft dendrites, and delineating an unusual cortical circuit in the RSC specialized for integrating long-range inhibition and thalamocortical excitation.

neuroscience↗

bioRxiv2018

Dorsal Hippocampal Activation Suppresses Neuropathic Pain Behaviors: Chronic pain as extinction-resistant pain-related memory traces

Accumulating evidence suggests the hippocampus being involved in, and modified with, chronic neuropathic pain. However, it is still not clear whether hippocampal activity has direct control over neuropathic behaviors. Here we show that activation of the dorsal, but not ventral, hippocampus, by glutamate microinjection or by chemogenetically increasing excitability (PSAM/PSEM), completely or partially reversed neuropathic behaviors: tactile allodynia and thermal hyperalgesia in the models of spared nerve injury and lumbar spinal nerve ligation. Using a new methodology (chemo-fMRI), where we combine awake resting state brain imaging with viral vector mediated chemogenetic activation (PSAM/PSEM), we could demonstrate that increased excitability of dorsal hippocampus neurons altered resting state functional connectivity within circuitry specifically related to the extent of diminution of neuropathic behavior (tactile allodynia). The identified circuitry most reliably (survived a validation procedure) identified dorsal hippocampal connections to the somatosensory cortex and the thalamus. Moreover, anterograde tracing indicated non-overlapping projections from dorsal and ventral hippocampus. Thus, the present study exhibits a novel causal role for the dorsal hippocampus, and mediating circuitry, controlling neuropathic pain-related behaviors. Altogether, these results imply downregulation of dorsal hippocampus circuitry in chronic neuropathic pain; the activation of which reverses pain behaviors either through disruption of accumulated memories and/or by enhancing extinction circuitry.

neuroscience↗