Naassila, M. | bioRxiv Science

bioRxiv2026

Acute lysergic acid diethylamide induces a time-dependent shift toward hippocampal control of default mode network reorganization

Background Classical psychedelics induce profound changes in brain function, yet the temporal organization of these effects remains incompletely understood. Methods We investigated the effects of acute lysergic acid diethylamide (LSD) on large-scale brain connectivity in nine male Long-Evans rats using resting-state functional magnetic resonance imaging. Following a 15-min baseline acquisition, rats received LSD (500 g/kg, i.p.), and imaging continued during two consecutive 15-min post-injection periods. Network reorganization was assessed using independent component analysis (ICA), seed-to-voxel mapping, stationary seed-to-seed connectivity, dynamic graph-based metrics, and dynamic causal modeling. Results LSD produced widespread but regionally heterogeneous changes across default mode network related, cortical, striatal, thalamic, sensory, and limbic systems. During the early post-injection window, ICA revealed a predominance of increased functional coupling, while dynamic analyses showed prominent fluctuations in hippocampal coupling strength and medial frontal network centrality. Dynamic causal modeling identified a false discovery rate-corrected reduction in retrosplenial-to-infralimbic influence, accompanied by a broader descriptive pattern of reduced posterior- and hippocampal-to-frontal coupling. During the later window, ICA showed a relative shift toward connectivity decreases, while complementary analyses revealed more selective hippocampal and parahippocampal involvement. Conclusions Across complementary analyses, acute LSD induced a temporally structured reorganization of brain hierarchy, characterized by an early weakening of directed cortical interactions followed by a later shift toward hippocampal-centered network control. These findings identify a dynamic shift in effective network organization and provide a mechanistic framework for psychedelic-induced default mode network reconfiguration.

neuroscience↗

bioRxiv2026

Schizophrenia-like neurodevelopmental pathology reshapes experience-dependent brain network remodeling following adolescent alcohol exposure

Background Alcohol use disorder (AUD) is highly prevalent in schizophrenia, yet the neurobiological basis of this vulnerability remains poorly understood. Neurodevelopmental models suggest that pre-existing brain dysconnectivity may increase vulnerability to AUD. We therefore tested whether schizophrenia-like neurodevelopmental pathology alters how alcohol-related experience is incorporated into large-scale brain networks. Methods Resting-state functional connectivity was assessed in male Sprague-Dawley rats (n = 18-21/group) with neonatal ventral hippocampal lesions (NVHL), a neurodevelopmental model of schizophrenia, and sham-operated controls, with or without voluntary adolescent alcohol exposure. Functional connectivity was assessed using seed-to-voxel and seed-to-seed analyses within a cortico-striato-limbic network. We additionally examined whether individual alcohol intake during adolescence predicted adult functional connectivity according to neurodevelopmental status. Results NVHL and adolescent alcohol exposure independently produced predominantly hypoconnected cortico-striato-limbic networks. However, alcohol exposure did not exacerbate NVHL-associated dysconnectivity but instead induced a distinct network reorganization characterized by functional hyperconnectivity. Although alcohol intake was comparable between groups, dose-dependent relationships between adolescent alcohol consumption and adult functional connectivity were observed in sham animals but were absent or markedly attenuated in NVHL rats. These effects were primarily centered on prelimbic cortex connectivity with the amygdala, hippocampus, and dorsal striatum, highlighting this circuitry as a major locus of altered experience-dependent remodeling. Conclusions These findings suggest that vulnerability to AUD associated with schizophrenia-like neurodevelopment may arise less from additive network dysfunction than from an altered capacity of large-scale brain networks for experience-dependent functional remodeling. Schizophrenia-like neurodevelopmental pathology may therefore change how alcohol-related experience is translated into persistent brain network organization.

neuroscience↗