Francisco José Urbano

Reversible protein acetylation controlled by histone deacetylases (HDACs) regulates neuronal gene expression and, increasingly, membrane physiology. We previously showed that pedunculopontine nucleus (PPN) gamma-band oscillations require class IIa HDAC activity, whereas class I inhibition was comparatively benign for that readout. Whether systemic HDAC inhibition acts uniformly across the forebrain, and across different neuronal nuclei, is unknown. Here we administered acute single systemic doses of the class I inhibitor MS275 (entinostat) and the class IIa inhibitor MC1568 to mice and performed whole-cell recordings in two functionally distinct, anatomically unconnected structures: medial prefrontal cortex (mPFC) and the ventrobasal complex (VB) of the thalamus. In mPFC pyramidal neurons we assessed short-term plasticity using paired-pulse stimulation and quantifying paired-pulse ratio (PPR); in VB neurons we quantified action-potential amplitude and the maximal rate of rise of the spike from phase-plot analysis. MS275 shifted PPR from facilitation toward depression on both mPFC and VB glutamatergic transmission, a significant change relative to vehicle, while MC1568 produced an intermediate, non-significant effect. In addition, MS275 reduced action-potential amplitude and markedly decreased the maximal rate of rise (dV/dt) of the spike in VB neurons. Thus, class I HDAC inhibition predominantly affected presynaptic glutamate release whilst affecting intrinsic properties of thalamocortical neurons. These results suggest that the consequences of systemic HDAC inhibition are class- and region-specific.

Although TREK1 channels are widely expressed in several thalamic nuclei, the role of this K _2P family member in modulating thalamic cell excitability and physiological thalamocortical oscillatory activity is not well studied. Here we explored the contribution of TREK1 channels to membrane properties of two important building blocks of the thalamocortical (TC) system, namely, GABAergic neurons of reticular thalamic nucleus (RTN) and TC neurons in different sensory thalamic nuclei including the ventrobasal complex (VB; somatosensory system) and the medial geniculate nucleus (MGN; auditory system), using male TREK1 knock-out (TREK1 ^−/− ) mice. Furthermore, we show that the loss of TREK1 channels has distinct effects on neuronal function in different thalamic nuclei. Compared with controls, TREK1 ^−/− mice exhibit decreased excitability in RTN neurons, while VB neurons maintain similar excitability levels. Additionally, the absence of TREK1 channels alters the action potential (AP) characteristics in VB TC neurons and affects GABAergic inhibitory tone in RTN neurons. In TREK1 ^−/− mice, the excitability of cortical pyramidal cells is increased. It is tempting to assume that this combination of changes contributes to a high number of sharp, spindle-like oscillations observed in sleep local field potential (LFP) recordings of these mice. In addition, TREK1 ^−/− mice show a lower amount of delta (1–4 Hz) oscillations during slow-wave sleep and a time-of-day-dependent alteration in the amount of sleep and wakefulness. They also show disturbed auditory signal processing and altered excitability in the auditory thalamus. These findings underline the relevance of TREK1 channels’ broad contribution to the thalamus and thalamocortical system.

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT_2A receptor (5-HT_2AR) in mice. In that regard, we used male and female, 5-HT_2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT_2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT_2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT_2AR blunted noribo-mediated responses to NMDA synaptic transmission.

The interactions between memory processes and emotions are complex. Our previous investigations in the crab Neohelice led to an adaptation of the affective extension of sometimes opponent processes (AESOP) model. The model proposes that emotions generate separate emotive memory traces, and that the unfolding of emotional responses is a crucial component of the behavioral expression of reactivated memories. Here, we show that an aversive conditioning, that used changes in an innate escape response to an aversive visual stimulus, induced an emotional behavior that endured beyond the stimuli: the aversive memory training built an anxiety-like state evaluated in a dark/light plus-maze. We found that, after the training session, crabs displayed aversion to maze light areas, and an increased time immobilized in the dark zones of the maze, an anxiety-like behavior induced by stressors or physiological conditions in other crustaceans. The training-dependent anxiety-like behavior was blocked by pretraining administration of fluoxetine, suggesting an underlying serotonin-dependent phenomenon. We hypothesize that this training-induced anxiety-like state generates a separate emotive memory trace that is reinstated and crucial for the modulation of memory expression once the memory is reactivated.

Rationale The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or “PACO” (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system. Objectives Our aim was to study ion conductances that have important implications regulating sleep–wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples (“PACO”-like binge”) using mice. Methods We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle. Results Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine (“PACO”-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic “PACO”-like administrations. Furthermore, intracellular basal [Ca²⁺] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type “window currents.” As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca²⁺ transients, regulated the membrane excitability, and altered sleep-wake transitions. Conclusion Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca²⁺].