Sex differences in cholinergic signaling affect functional outcomes for theta-gamma coordination in hippocampal subcircuits following experimental febrile status epilepticus.

OBJECTIVE: Sex determines cognitive outcome in animal models of early life seizure, where males exhibit impaired hippocampal-dependent learning and memory compared with females. The physiological underpinnings of this sex effect are unclear. Cholinergic signaling is essential for the generation of hippocampal oscillations, and supplementation of cholinergic precursors prior to status epilepticus in immature male rats prevents subsequent memory deficits. We hypothesized that there are sex differences in acetylcholine circuits and their response to experimental febrile status epilepticus (eFSE). METHODS: eFSE was induced in male and female rat pups. We transversed the hippocampus of postnatal day >60 control (CTL) and eFSE rats with a 64-channel laminar silicon probe to assay cholinergic-dependent theta oscillations under urethane anesthesia. Local field potential properties were compared during (1) baseline sensory stimulation, (2) pharmacological stimulation via acetylcholine reuptake blockade, and (3) sensory stimulation after muscarinic acetylcholine receptor block (atropine). RESULTS: In all groups, a baseline tail pinch could elicit theta oscillations via corticohippocampal synaptic input. Following atropine, a tail pinch response could no longer be elicited in CTL male, CTL female, or eFSE female rats. In contrast, induced slow theta power in eFSE males after atropine was not decreased to spontaneous levels. Analysis of oscillation bandwidths revealed sex differences in acetylcholine modulation of theta frequency and slow gamma frequency and power. This study also identified significant effects of both sex and eFSE on baseline theta-gamma comodulation, indicating a loss of coupling in eFSE males and a potential gain of function in eFSE females. SIGNIFICANCE: There are differences in cholinergic modulation of theta and gamma signal coordination between male and female rats. These differences may underlie worse cognitive outcomes in males following eFSE. Promoting the efficacy of muscarinic acetylcholine signaling prior to or following early life seizures could elucidate a mechanism for the temporal discoordination of neural signals within and between hippocampus and neocortex and provide a novel therapeutic approach for improving cognitive outcomes.

CBD treatment following early life seizures alters orbitofrontal-striatal signaling during adulthood.

Obsessive compulsive disorder (OCD) is a comorbid condition of epilepsy and often adds to the burden of epilepsy. Both OCD and epilepsy are disorders of hyperexcitable circuits. Fronto-striatal circuit dysfunction is implicated in OCD. Prior work in our laboratory has shown that in rat pups following a series of flurothyl-induced early life seizures (ELS) exhibit frontal-lobe dysfunction along with alterations in electrographic temporal coordination between the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), circuits implicated in OCD. Here, we studied the effects of ELS in male and female rat pups on OCD-like behaviors as adults using the marble burying test (MBT). Because cannabidiol (CBD) is an effective antiseizure medication and has shown efficacy in the treatment of individuals with OCD, we also randomized rats to CBD or vehicle treatment following ELS to determine if CBD had any effect on OCD-like behaviors. While the flurothyl model of ELS did not induce OCD-like behaviors, as measured in the MBT, ELS did alter neural signaling in structures implicated in OCD and CBD had sex-dependent effects of temporal coordination in a way which suggests it may have a beneficial effect on epilepsy-related OCD.

Differences in Sleep EEG Coherence and Spindle Metrics in Toddlers With and Without Language Delay: A Prospective Observational Study.

Background: Sleep plays a crucial role in early language development, and sleep disturbances are common in children with neurodevelopmental disorders. Examining sleep microarchitecture in toddlers with and without language delays can offer key insights into neurophysiological abnormalities associated with atypical neurodevelopmental trajectories and potentially aid in early detection and intervention. Methods: Here, we investigated electroencephalogram (EEG) coherence and sleep spindles in 16 toddlers with language delay (LD) compared with a group of 39 typically developing (TD) toddlers. The sample was majority male (n = 34, 62%). Participants were aged 12-to-22 months at baseline, and 34 (LD, n=11; TD, n=23) participants were evaluated again at 36 months of age. Results: LD toddlers demonstrated increased EEG coherence compared to TD toddlers, with differences most prominent during slow-wave sleep. Within the LD group, lower expressive language skills were associated with higher coherence in REM sleep. Within the TD group, lower expressive language skills were associated with higher coherence in slow-wave sleep. Sleep spindle density, duration, and frequency changed between baseline and follow-up for both groups, with the LD group demonstrating a smaller magnitude of change than the TD group. The direction of change was frequency-dependent for both groups. Conclusions: These findings indicate that atypical sleep EEG connectivity and sleep spindle development can be detected in toddlers between 12 and 36 months and offers insights into neurophysiological mechanisms underlying the etiology of neurodevelopmental disorders. Trial registration: https://clinicaltrials.gov/study/NCT01339767; Registration date: 4/20/2011.