Biology subjects

Puig, M. V.

Publications and source records attributed to Puig, M. V..

6 recordsLinked to original sources

bioRxiv2026

A Reproducible Cortical Model of Focal Epileptiform Activity with a Multi-Biomarker Analysis Pipeline

The development of surface-based therapeutic strategies, including extracranial illumination and epicortical electrical or optoelectronic neuromodulation, requires experimental models in which focal pathological activity can be generated and monitored within an accessible cortical region. Here, we established an acute cortical model of focal epileptiform activity in anesthetized mice based on local microinjection of 4-aminopyridine (4-AP) into the barrel cortex. This preparation provides precise spatial and temporal control of the epileptiform focus while enabling simultaneous electrophysiological sampling across cortical depth. To objectively characterize the induced activity, we implemented a Python-based analysis pipeline integrating complementary electrophysiological biomarkers, including oscillatory power, multi-unit activity, pathological fast ripples (250-650 Hz), and epileptiform bursts. Local 4-AP administration produced robust increases in gamma (30-100 Hz) power, multi-unit firing (MUA), fast ripple and burst activity. Pharmacological sensitivity of the framework was evaluated using carbamazepine, which robustly attenuated 4-AP-induced increases in all biomarkers. Together, this study provides a reproducible experimental and analytical framework for investigating focal cortical epileptiform activity and for the future evaluation of pharmacological, optical, and electrical interventions targeting superficial cortical networks.

neuroscience↗

bioRxiv2025

Cellular mechanisms underlying the pro-cognitive effects of serotonin 5-HT7 receptors in a mouse model of schizophrenia

Serotonin 5-HT7 receptors (5-HT7Rs) have emerged as promising targets for treating cognitive and affective disturbances in schizophrenia and other neuropsychiatric disorders, yet their cellular substrates and circuit-level mechanisms remain poorly defined. Here, we combined immunohistochemistry, multisite electrophysiology, and behavioral assays to investigate how 5-HT7Rs modulate hippocampal-prefrontal pathways in healthy mice and in a subchronic phencyclidine (sPCP) model of cognitive and negative symptoms in schizophrenia. We found that 5-HT7Rs are abundantly expressed in both excitatory and inhibitory neurons of the dorsal hippocampus (dHPC) and medial prefrontal cortex (mPFC), with high co-expression in PV and SST interneurons ([~]80% in dHPC; 55% PV and 75% SST in mPFC). In healthy mice, systemic 5-HT7R activation with the agonist AS-19 suppressed neuronal activity and synchrony within dHPC (CA1) - mPFC (PL) pathways, reducing theta and high-gamma power, theta-gamma coupling in CA1, theta coherence, and CA1[->]PL directional connectivity, consistent with recruitment of inhibitory microcircuits. The similarity between 5-HT7R-mediated inhibition and the circuit effects we previously described for 5-HT1AR activation, together with evidence for 5-HT7R-5-HT1AR heterodimerization, suggests that these receptors act in concert to dynamically constrain hippocampal-prefrontal circuits. sPCP treatment induced persistent recognition-memory impairments, heightened anxiety-like behavior, and pathological high-frequency synchronization of hippocampal-prefrontal networks. Blockade of 5-HT7Rs with SB-269970 or the atypical antipsychotic lurasidone (but not lurasidone combined with AS-19) rescued memory performance, reduced anxiety-like behavior, and normalized aberrant high-frequency hypersynchrony, while enhancing CA1[->]PL theta signaling immediately before memory acquisition. Together, these findings indicate that 5-HT7R activation exerts potent inhibitory control over hippocampal-prefrontal pathways, likely via PV and SST interneurons, and suggest that 5-HT7R blockade constitutes a promising therapeutic strategy to restore excitation-inhibition balance and enhance neural communication within brain circuits crucial for cognition and mood regulation in neuropsychiatric disorders.

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

Graphene-based thin film microelectrode technology for in vivo high resolution neural recording and stimulation

Neuroprosthetic technology aims to restore nervous system functionality in cases of severe damage or degeneration by recording and stimulating the electrical activity of the neural tissue. One of the key factors determining the quality of the neuroprostheses is the electrode material used to establish electrical communication with the neural tissue, which is subject to strict electrical, electrochemical, and mechanical specifications as well as biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin film technology and its engineering to form flexible neural implants. Bench measurements show that the developed microelectrodes offer low impedance and high charge injection capacity throughout millions of pulses. In vivo electrode performance was assessed in rodents both from brain surface and intracortically showing high-fidelity recording performance, while stimulation performance was assessed with an intrafascicular implant that demonstrated low current thresholds and high selectivity for activating subsets of axons within the sciatic nerve. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical and intraneural implantation. Overall, this works describes a novel graphene-based thin film microelectrode technology and demonstrates its potential for high-precision neural interfacing in both recording and stimulation applications.

bioengineering↗

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↗