Biology subjects

Lorincz, M. L.

Publications and source records attributed to Lorincz, M. L..

11 recordsLinked to original sources

bioRxiv2025

Heterogeneity of ictal firing during generalized seizures in the awake cortex

Cortico-thalamo-cortical oscillations are central to both normal and pathological brain activities and emerge from complex cortical and thalamic interactions. However, the specific activity of identified cortical neurons during the paroxysmal oscillations associated with absence seizures (ASs) in awake animals remains underexplored. The dominant narrative suggests that seizures indiscriminately disrupt cortical activity through generalized hyperexcitability, but direct evidence supporting this view is lacking. Here, we recorded single units from pyramidal neurons and different interneuron subtypes in the neocortex of two validated rodent models of absence epilepsy under awake, behaving conditions. We find that neurons maintain their firing rank order across interictal and ictal states, regardless of whether their ictal firing rate increases, decreases, or remains stable compared to the interictal phase. Rather than a random cortical takeover, ictal activity represents a scalable modulation of pre-existing network states. These results challenge the generalized hyperexcitability model and highlight the structured, heterogeneous nature of cortical activity during ASs, with implications for mechanistic understanding and targeted therapies.

neuroscience↗

bioRxiv2025

A thalamic circuit mechanism for stress-dependent modulation of REM sleep

Rapid eye movement (REM) sleep, a brain state critical for sleep quality and cortical cognition, is tightly controlled by brainstem circuits and highly sensitive to stress. Yet, how these systems interact to regulate REM sleep and its associated forebrain rhythms remains elusive. Here, we identify a thalamic hub that conveys medullary REM-promoting signals, and integrates stress inputs to regulate REM sleep. A subpopulation of paraventricular thalamic neurons that collaterally project to the cortex and nucleus accumbens (PVT[->]NAc) selectively responds to activation of medulla REM-promoting neurons, and bidirectionally modulates REM-associated theta oscillations in an activity-dependent manner. Their low-frequency activation promotes theta rhythms during REM sleep, while high-frequency activation suppresses them, mirroring the neuronal signatures of acute and chronic stress, respectively. Distinct patterns of PVT[->]NAc neurons underlie the bidirectional stress modulation of REM sleep, partly by differentially engaging prefrontal microcircuits via their collateral projections. Together, our findings uncover a thalamic integrative hub that couples sleep-regulating and stress pathways to adaptively control REM sleep expression.

neuroscience↗

bioRxiv2025

Non-vectorial Integration of Intersectional Short-Pulse Stimulation Enables Enhanced Deep Brain Modulation and Effective Seizure Control

Transcranial electrical stimulation (TES) holds promise to treat neurological disorders, but its efficacy is limited by poor spatial focality and depth of penetration. Here, we examined the potential utility of Intersectional Short-Pulse (ISP) stimulation of deeper brain penetration. Using computational modeling and in vivo patch-clamp recordings in rats, we demonstrate that neurons integrate ISP-induced electric fields in a non-vectorial manner. This mechanism allows ISP to overcome some limits of conventional TES, achieving spatially limited stimulation across cortical and subcortical structures. In a rat model of temporal lobe epilepsy, closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 49% and 41% compared to sham stimulation and conventional TES and significantly reduced motor seizure severity. Our findings demonstrate that ISP stimulation can rapidly terminate hippocampal seizures, offering a potential new approach for non-invasive neuromodulation with applications across diverse neurologic and psychiatric disorders.

neuroscience↗

bioRxiv2024

Neuronal phenotype defined by transcriptome-wide bursting kinetics in pyramidal and fast-spiking cells

Single-cell sequencing revealed the transcriptional heterogeneity of neurons and introduced transcriptome-defined neuron types and subtypes. Temporal recordings of gene transcription showed that mRNA synthesis is arranged into transcriptional bursts which can be characterized by kinetic parameters. Here, we selected two distinct, functionally homogenous, and electrophysiologically well-defined neuronal cell types - the pyramidal cells and fast-spiking interneurons - for transcriptional burst analysis. Hierarchical clustering based on electrophysiological parameters recovered these cell types. In contrast, clustering based on transcripts failed to differentiate these neuronal phenotypes. We applied mathematical models to analyze burst kinetics of fast-spiking and pyramidal cells to explore the transcriptional underpinning of their distinct physiological functions. We found that inferred burst kinetic parameters are distinct measures of gene expression from average mRNA counts. Based on our results, we suggest that burst kinetics can be considered as a component of transcriptome-defined neuronal phenotype besides mRNA counts.

bioinformatics↗

bioRxiv2024

Hippocampal sharp wave ripples mediate generalization and subsequent fear attenuation via closed-loop brain stimulation in rats

The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD.

neuroscience↗

bioRxiv2022

Closed-loop brain stimulation to reduce pathologic fear

Maladaptive processing of trauma related memory engrams leads to dysregulated fear reactions. In post-traumatic stress disorder (PTSD), dysfunctional extinction learning prevents discretization of trauma-related memory engrams and leads to generalized fear responses. PTSD is postulated as a mnemonic-based disorder, but we lack markers or treatments targeting pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. We demonstrate that closed-loop SWRs triggered neuromodulation of the medial forebrain bundle (MFB) can enhance the consolidation of fear extinction. It modified fear memories that became resistant to induced recall (i.e., renewal and reinstatement) and did not reemerge spontaneously as a PTSD-like phenotype. The effects are mediated by D2 receptor signaling induced synaptic remodeling in the basolateral amygdala. These results suggest that SWRs help consolidating fear extinction memories. Furthermore, enhancing the consolidation of extinction engrams by SWR-triggered induction of reward signals can alleviate pathologic fear reactions in a rodent model of PSTD. No adverse effects were seen, suggesting this potential therapy for PTSD and anxiety disorders.

neuroscience↗

bioRxiv2022

Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression

Although the etiology of major depressive disorder remains poorly understood, impairment of gamma oscillations recently emerged as a potential biomarker for major depression. The olfactory bulb (OB) is a major source of brain wide gamma oscillations and bulbectomy is an animal model for depression. Here we demonstrate that chemogenetic suppression of OB neuronal activity or temporally suppressing the OB to pyriform cortex synaptic transmission decreased gamma oscillation power in multiple brain areas associated with depression-like behaviors. To assess the hypothesized link between depression and diffuse depression of gamma oscillations, we employed gamma phase-dependent closed loop neuromodulation of cortical areas, paced by the native OB output. This procedure alleviated depressive-like behaviors in animals and suggests that restoring gamma oscillations may improve depression in humans. One Sentence SummaryRole of limbic gamma oscillations in depression

neuroscience↗

bioRxiv2022

Differential serotonergic modulation of principal neurons and interneurons in the anterior piriform cortex

Originating from the brainstem raphe nuclei, serotonin is an important neuromodulator involved in a variety of physiological and pathological functions. Specific optogenetic stimulation of serotonergic neurons results in the divisive suppression of spontaneous, but not sensory evoked activity in the majority of neurons in the primary olfactory cortex and an increase in firing in a minority of neurons. To reveal the mechanisms involved in this dual serotonergic control of cortical activity we used a combination of in vitro electrophysiological recordings from identified neurons in the primary olfactory cortex, optogenetics and pharmacology and found that serotonin suppressed the activity of principal neurons, but excited local interneurons. The results have important implications in sensory information processing and other functions of the olfactory cortex and related brain areas.

neuroscience↗

bioRxiv2021

Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures

ObjectiveHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a pro-absence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, that is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection in the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. MethodsWe used EEG recordings in freely moving Genetic Absence Epilepsy from Strasbourg Rats (GAERS) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected in the CIN and VB of GAERS in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical layer 5/6 and thalamocortical neurons, respectively. ResultsOral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection in CIN abolished ASs and elicited small-amplitude 4-7 Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN-channel-dependent properties of cortical layer 5/6 pyramidal and thalamocortical neurons, respectively. SignificanceThese results provide the first demonstration of the anti-absence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

neuroscience↗

bioRxiv2021

Cell-type specific arousal-dependent modulation of thalamic activity in the lateral geniculate nucleus

State dependent thalamocortical activity is important for sensory coding, oscillations and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state dependent spontaneous and visually evoked activity of LGN neurons in awake behaving animals remains controversial. Using a combination of pupillometry, extracellular and intracellular recordings from identified LGN neurons we show that thalamocortical neurons and interneurons are distinctly correlated to arousal forming two complementary coalitions. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback to the LGN suppressed the arousal dependency of LGN neurons. Taken together our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal dependent brain states in awake mice and this might have important functional implications.

neuroscience↗

bioRxiv2020

Disinhibition mediated by reciprocal hypothalamic and raphe GABAergic projections promotes wakefulness

The lateral hypothalamus (LH), together with multiple neuromodulatory systems of the brain, such as the dorsal raphe nucleus (DR), is implicated in arousal, yet interactions between these systems are just beginning to be explored. Using a combination of viral tracing, circuit mapping, electrophysiological recordings from identified neurons and combinatorial optogenetics in mice, we show that GABAergic neurons in the LH selectively inhibit GABAergic neurons in the DR resulting in increased firing of a substantial fraction of its neurons that ultimately promotes arousal. These DRGABA neurons are wake active and project to multiple brain areas involved in the control of arousal including the LH, where their specific activation potently influences local network activity leading to arousal from sleep. Our results show how mutual inhibitory projections between the LH and the DR promote wakefulness and suggest a complex arousal control by intimate interactions between long-range connections and local circuit dynamics.

neuroscience↗