Biology subjects

Gener, T.

Publications and source records attributed to Gener, T..

5 recordsLinked to original sources

bioRxiv2023

Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A

Abnormal dendritic arbors, dendritic spine "dysgenesis" and excitation inhibition imbalance are main traits assumed to underlie impaired cognition and behavioral adaptation in intellectual disability. However, how these modifications actually contribute to functional properties of neuronal networks, such as signal integration or storage capacity is unknown. Here, we used a mouse model overexpressing Dyrk1A (Dual-specificity tyrosine [Y]-regulated kinase), one of the most relevant Down syndrome (DS) candidate genes, to gather quantitative data regarding hippocampal neuronal deficits produced by the overexpression of Dyrk1A in mice (TgDyrk1A; TG). TG mice showed impaired hippocampal recognition memory, altered excitation-inhibition balance and deficits in hippocampal CA1 LTP. We also detected for the first time that deficits in dendritic arborization in TG CA1 pyramidal neurons are layer-specific, with a reduction in the width of the stratum radiatum, the postsynaptic target site of CA3 excitatory neurons, but not in the stratum lacunosum-moleculare, which receives temporo-ammonic projections. To interrogate about the functional impact of layer-specific TG dendritic deficits we developed tailored computational multicompartmental models. Computational modelling revealed that neuronal microarchitecture alterations in TG mice lead to deficits in storage capacity, altered the integration of inputs from entorhinal cortex and hippocampal CA3 region onto CA1 pyramidal cells, important for coding place and temporal context and on connectivity and activity dynamics, with impaired the ability to reach high {gamma} oscillations. Contrary to what is assumed in the field, the reduced network activity in TG is mainly contributed by the deficits in neuronal architecture and to a lesser extent by over-inhibition. Finally, given that therapies aimed at improving cognition have also been tested for their capability to recover dendritic spine deficits and excitation-inhibition imbalance, we also tested the short- and long-term changes produced by exposure to environmental enrichment (EE). Exposure to EE normalized the excitation inhibition imbalance and LTP, and had beneficial effects on short-term recognition memory. Importantly, it produced massive but transient dendritic remodeling of hippocampal CA1, that led to recovery of high {gamma} oscillations, the main readout of synchronization of CA1 neurons, in our simulations. However, those effects where not stable and were lost after EE discontinuation. We conclude that layer-specific neuromorphological disturbances produced by Dyrk1A overexpression impair coding place and temporal context. Our results also suggest that treatments targeting structural plasticity, such as EE, even though hold promise towards improved treatment of intellectual disabilities, only produce temporary recovery, due to transient dendritic remodeling.

neuroscience↗

bioRxiv2023

Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and rescue by risperidone

NMDAR hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and perceptual impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory perception and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the new object and its short-term storage were associated with mPFC[->]dHPC high gamma connectivity whereas long-term memory retrieval depended on dHPC[->]mPFC theta connectivity. sPCP impaired short-term and long-term memory, which was associated with increased mPFC and decreased dHPC neural network activities, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and attenuated hippocampal desynchronization. sPCP also impaired auditory perception and its neural correlates (evoked potentials and MMN) in the mPFC, which were also ameliorated by risperidone. Our study suggests that during NMDAR hypofunction the mPFC and the dHPC disconnect possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

neuroscience↗

bioRxiv2022

Prefrontal accumbens neural dynamics abnormalities in mice vulnerable to develop food addiction

Food addiction is characterized by a loss of behavioral control over food intake and is closely associated with several eating disorders, including obesity and binge eating. Despite its high prevalence, the underlying neural mechanisms of food addiction are still unresolved. We trained mice in an operant paradigm for 110 days to promote the development of food addiction. Then, we classified mice as addicted and extreme non-addicted based on three addiction criteria and recorded neural activities in the prelimbic medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) core through electrophysiology in vivo. Addicted mice presented disrupted mPFC-to-NAc signaling at high frequencies (hfo 150-200 Hz) during decision-making to obtain food. Moreover, addicted mice exhibited reduced low gamma oscillations and theta-gamma coupling in the NAc during reward expectancy. Disrupted mPFC-to-NAc connectivity and gamma synchrony in the NAc correlated with increased reinforcement levels, unraveling the functional relevance of these alterations. The cannabinoid type-1 (CB1) receptor antagonist rimonabant rescued neural alterations observed in the addicted mice.Reinforcement levels were reduced after rimonabant administration and the directionality of signals and oscillatory activity in the NAc were reversed in addicted mice during decision-making and reward expectation, respectively. These findings suggest that disrupted mPFC-NAc neural dynamics are candidate mechanisms underlying specific behavioral alterations associated with food addiction. The elucidation of these novel communication mechanisms between the mPFC and the NAc will provide advances towards future development of new therapeutic interventions for food addiction and related disorders.

animal behavior and cognition↗

bioRxiv2022

Postnatal environmental enrichment enhances memory by shaping hippocampal-prefrontal theta and gamma rhythms in diploid and trisomic female mice

Rich social, physical, and cognitively stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to attenuate cognitive impairment due to intellectual disability, but also aging and neurodegeneration, however the underlying neural mechanisms are poorly understood. Here we investigated the neural substrates of memory amelioration induced by postnatal environmental enrichment (EE) in diploid female mice and Ts65Dn female mice with partial trisomy of genes ortholog to human chromosome 21, a standard model of Down syndrome (DS, trisomy 21). We recorded neural activities in two brain structures key for cognitive function, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in standard or enriched environments for 7 weeks post-weaning. We found that EE shaped hippocampal- prefrontal neural dynamics in diploid mice and rescued the same disrupted pathways in Ts65Dn mice. The neural activity changes detected in EE-reared wild-type mice combined task-independent adjustments (augmented hippocampal pyramidal activity and gamma synchrony across different brain states) and memory-dependent adjustments (enhanced theta-gamma coupling and ripples in the HPC). Therefore, both brain state adjustments and memory-associated adjustments are good candidates to underlie the beneficial effects of EE on cognition in diploid female mice. Concomitantly, EE attenuated hippocampal and prefrontal hypersynchrony in trisomic females, suggesting distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE. These results put forward hippocampal hypersynchrony and hippocampal-prefrontal miscommunication as major neural mechanisms underlying the beneficial effects of EE for intellectual disability in DS.

neuroscience↗

bioRxiv2021

Phencyclidine-induced psychosis causes hypersynchronization and disruption of connectivity within prefrontal-hippocampal circuits that is rescued by antipsychotic drugs

Neural synchrony and functional connectivity are disrupted in neuropsychiatric disorders such as schizophrenia. However, these alterations and how they are affected by commonly prescribed neuropsychiatric medication have not been characterized in depth. Here, we investigated changes in neural dynamics of circuits involving the prefrontal cortex and the hippocampus during psychosis induced by the NMDAR antagonist phencyclidine and subsequent recovery by three different antipsychotic drugs (APDs), the classical APD haloperidol and two atypical APDs, clozapine and risperidone, in freely moving mice. We found that the psychotomimetic effects of phencyclidine were associated with hypersynchronization and disrupted communication of prefrontal-hippocampal pathways. Major alterations occurred in the prefrontal cortex, where phencyclidine increased oscillatory power at delta, high gamma and high frequencies (<100 Hz) and generated aberrant cross-frequency coupling, suggesting the presence of hypersynchronous cortical microcircuits. Cross-regional coupling and phase coherence were also enhanced, further reflecting that the circuits functional connectivity was increased. Phencyclidine also redirected the intrinsic flow of information at theta frequencies that traveled from the hippocampus to the prefrontal cortex into delta rhythms that traveled in the opposite direction. The three APDs rescued most phencyclidine-induced changes in power, coupling, phase coherence, and directionality, suggesting common cellular mechanisms of antipsychotic action. However, some differential effects were identified, likely resulting from the distinct affinity the three APDs have for dopamine and serotonin receptors. We therefore investigated how serotonin 1A (5-HT1AR) and 2A receptors (5-HT2AR) compare to the actions of the APDs. 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT rescued phencyclidine-induced increased power, coupling and phase coherence but were unable to normalize the circuits theta directionality. This suggests that other targets of the AAPDs working in tandem with 5-HT1ARs and 5-HT2ARs are required to ameliorate this key feature of the circuit.

neuroscience↗