Biology subjects

Turi, G.

Publications and source records attributed to Turi, G..

4 recordsLinked to original sources

bioRxiv2026

Hippocampo-septal inhibitory feedback controls the medial septal circuit as a function of brain state, pyramidal cell activity and movement speed.

Encoding novel experiences and retrieving stored information rely on the hippocampal theta rhythm in several mammalian species. Coordination of putative pacemakers in the medial septum (MS) by the GABAergic hippocampo-septal (HS) feedback is hypothesized to be essential for theta genesis. In order to reveal how the HS-feedback controls the MS circuit, and through it hippocampal oscillations in general, we set out to uncover the behavior-related activity of HS neurons as well as how different components of the MS network are regulated by the HS-feedback. Utilizing computational modelling and in vivo optogenetic manipulation of the HS pathway, we show that the HS feedback is not required for theta generation, which is primarily governed by intra-MS connections. HS blockade did not alter the phase coupling of MS neurons to hippocampal theta rhythm nor the synchrony between rhythmic MS neurons but augmented ongoing theta and coupled mid-gamma oscillations in the hippocampus. By contrast, correlated activity between non-rhythmic MS neurons was sensitive to HS blockade. Moreover, the HS feedback scaled with hippocampal activity and running speed. In turn, modulation of MS neurons by running and ripples was diminished by the transient suppression of HS terminals. These findings suggest that the HS feedback exerts inhibitory control of the MS depending upon hippocampal output and movement speed.

neuroscience↗

bioRxiv2025

Novel, small molecules targeting the 5-HT4R receptor protect against stress-induced maladapative behavior with efficacy across age

BACKGROUNDStress is a risk factor for developing psychiatric disorders, including major depressive disorder (MDD). Compounds targeting the serotonin type 4 receptor (5-HT4R) hold promise as novel rapid-acting treatments of mood disorders. However, a lack of selectivity and numerous side effects have been limiting factors for their clinical use. Here, we developed and characterized novel-composition 5-HT4R compounds in mouse models of stress. METHODSThree 5-HT4R-targeting compounds were designed and synthesized based on PF-04995274, a high-affinity 5-HT4R ligand reported to be a partial agonist. G-protein assays were utilized to characterize molecular activity. Saline, PF-04995274, or a novel compound were administered before or after stress in male and female mice. Drug effects were assayed using behavioral paradigms. Patch clamp electrophysiology was used to determine the effect of drug on glutamatergic activity in hippocampal Cornu Ammonis 3 (CA3). RESULTSProphylactic administration of DL5, DL7, or DL8 was effective at reducing stress-induced maladaptive behaviors in male and female mice; DL7 and DL8 were effective when administered after stress. When administered following learned helplessness (LH), DL7 reduced behavioral despair and increased c-Fos in the dentate gyrus (DG) and CA3. All novel compounds attenuated large-amplitude AMPA receptor-mediated bursts in ventral CA3 (vCA3). In aged male mice, prophylactic DL7 reduced behavioral despair. CONCLUSIONSThese results characterize novel 5-HT4R-targeting compounds for stress-induced psychiatric disease with the potential to address unmet needs in adult and aged patients with stress-induced psychiatric illness. Future work will characterize their mechanism of action with the goal of clinical development.

neuroscience↗

bioRxiv2025

Antidepressants promote developmental-like plasticity through remodeling of extracellular matrix

Antidepressants are widely used to treat mood and anxiety disorders, yet the cellular and molecular mechanisms underlying their therapeutic effects remain poorly understood. Here, we show that the selective serotonin reuptake inhibitor (SSRI) fluoxetine rejuvenates the dentate gyrus (DG) by reactivating a latent developmental plasticity program in mature neurons, which is required for re-engaging critical period-like synaptic remodeling and antidepressant-like behavioral effects. Single nuclei transcriptomic profiling across all hippocampal cell types revealed a strikingly selective response in the DG, where mature neurons re-engaged a developmental-like transcriptional state, an effect distinct from adult neurogenesis. Chronic fluoxetine treatment induced expression of SOX11, a developmental transcription factor involved in neurodevelopment and axonal regeneration that is normally silenced in the adult brain. Reactivation of SOX11 in mature DG neurons was necessary for both the antidepressant-like behavioral effects of fluoxetine and the re-engagement of critical period-like synaptic remodeling. Notably, SOX11 reactivation was also induced by physiological stimuli, including environmental enrichment and peripheral axon regeneration, suggesting that mature neurons retain access to a conserved developmental plasticity program throughout adulthood. We further identified evidence of this form of developmental plasticity in the adult human brain, an effect distinct from adult neurogenesis. At the structural level, fluoxetine remodeled novel extracellular matrix (ECM) structures within the DG distinct from canonical perineuronal nets, and targeted ECM degradation was sufficient to reactivate SOX11 in mature neurons, identifying the ECM as a key regulator of neuronal rejuvenation. Altogether, these findings demonstrate that mature neurons retain an intrinsic capacity to re-engage dormant developmental programs, and that antidepressants harness this regenerative plasticity to drive neural circuit remodeling and antidepressant-like effects.

neuroscience↗

bioRxiv2020

Parallel processing of sensory cue and spatial information in the Dentate Gyrus

During exploration, animals form an internal map of an environment by combining information about specific sensory cues or landmarks with the animals motion through space, a process which critically depends on the mammalian hippocampus. The dentate gyrus (DG) is the first stage of the hippocampal trisynaptic circuit where self-motion and sensory cue information are integrated, yet it remains unknown how neurons within the DG encode both cue related ("what") and spatial ("where") information during cognitive map formation. Using two photon calcium imaging in head fixed mice running on a treadmill, along with on-line sensory cue manipulation at specific track locations, we have identified robust sensory cue responses in DG granule cells largely independent of spatial location. Granule cell cue responses are stable for long periods of time, selective for the modality of the stimulus and accompanied by strong inhibition of the firing of other active neurons. At the same time, there is a smaller fraction of neurons whose firing is spatially tuned but insensitive to the presentation of nearby cues, similar to traditional place cells. These results demonstrate the existence of "cue cells" in addition to the better characterized "place cells" in the DG, an important heterogeneity that has been previously overlooked. We hypothesize that the granule cell population may support multiple channels of spatial and non-spatial information that contribute distinctly to local and down-stream computations and impact the role of the dentate gyrus in spatial navigation and episodic memory.

neuroscience↗