Methylmercury plus Ethanol Exposure: How Much Does This Combination Affect Emotionality?

Mercury is a heavy metal found in organic and inorganic forms that represents an important toxicant with impact on human health. Mercury can be released in the environment by natural phenoms (i.e., volcanic eruptions), industrial products, waste, or anthropogenic actions (i.e., mining activity). Evidence has pointed to mercury exposure inducing neurological damages related to emotional disturbance, such as anxiety, depression, and insomnia. The mechanisms that underlie these emotional disorders remain poorly understood, although an important role of glutamatergic pathways, alterations in HPA axis, and disturbance in activity of monoamines have been suggested. Ethanol (EtOH) is a psychoactive substance consumed worldwide that induces emotional alterations that have been strongly investigated, and shares common pathophysiological mechanisms with mercury. Concomitant mercury and EtOH intoxication occur in several regions of the world, specially by communities that consume seafood and fish as the principal product of nutrition (i.e., Amazon region). Such affront appears to be more deleterious in critical periods of life, such as the prenatal and adolescence period. Thus, this review aimed to discuss the cellular and behavioral changes displayed by the mercury plus EtOH exposure during adolescence, focused on emotional disorders, to answer the question of whether mercury plus EtOH exposure intensifies depression, anxiety, and insomnia observed by the toxicants in isolation.

Hypo- and hyper- sensory processing heterogeneity in Autism Spectrum Disorder

Background. Sensory processing atypicalities are part of the core symptoms of autism spectrum disorder (ASD) and could result from an excitation/inhibition imbalance. Yet, the convergence level of phenotypic sensory processing atypicalities with genetic alterations in GABA-ergic and glutamatergic pathways remains poorly understood. This study aimed to characterize the distribution of hypo/hyper-sensory profile among individuals with ASD and investigate the role of deleterious mutations in GABAergic and glutamatergic pathways related genes in sensory processing atypicalities. Method. From the Short Sensory Profile (SSP) questionnaire, we defined and explored a score – the differential Short Sensory Profile (dSSP) - as a normalized and centralized hypo/hypersensitivity ratio for 1136 participants (533 with ASD, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP). We also performed an unsupervised item-based clustering analysis on SSP items scores to validate this new categorization in terms of hypo and hyper sensitivity. We then explored the link between the dSSP score and the burden of deleterious mutations in a subset of individuals for which whole-genome sequencing data were available. Results. We observed a mean dSSP score difference between ASD and controls, driven mostly by a high dSSP score variability among groups (PARIS: p<0.0001, η2 = 0.0001, LEAP: p<0.0001, Cohen’s d=3.67). First-degree relatives were with an intermediate distribution variability profile (p<0.0001). We also reported a positive developmental trajectory of the dSSP score (PARIS: p=0.0006, η2 = 0.02; LEAP: p=0.01, η2 = 0.01). Clusters were similarly characterized by hypo- and hyper-sensitivity items in both study samples (Cramer's V from 0.64 to 0.69, p<0.05). Our genetic analysis showed a trend only for an association with mutations of the GABAergic pathway.Limitations. The major limitation was the dSSP score difficulty to discriminate subjects with a similar quantum of hypo- and hyper- sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0.Conclusion. The dSSP score could be a relevant clinical score of the hypo/hyper-sensory individual profile in subjects with ASD. Combined with additional sensory domain characteristics, genetics and endophenotypic substrates, the dSSP score will offer new avenues to explore the underlying neurobiological mechanisms of sensory processing atypicalities in ASD.

Novel Ca2+-modulated Photoactivatable Imaging Reveals Neuron-Astrocyte Glutamatergic Circuitries within the Nucleus Accumbens

Astrocytes are key elements of brain circuits that are involved in different aspects of the neuronal physiology relevant to brain functions. Although much effort is being made to understand how the biology of astrocytes affects brain circuits, astrocytic network heterogeneity and plasticity is still poorly defined. Here, we have combined structural and functional imaging of astrocyte activity using the Ca2+-modulated photoactivatable ratiometric integrator and specific optostimulation of glutamatergic pathways to map the functional neuron-astrocyte circuitries in the nucleus accumbens (NAc). We showed pathway-specific astrocytic responses induced by selective optostimulation of main inputs from the prefrontal cortex, basolateral amygdala, and ventral hippocampus. Furthermore, the differences in basal Ca2+ dynamics between the NAc shell and core astrocytes were associated with differences in mitochondrial DNA copy number, exhibiting molecular heterogeneity in the regulation of their mitochondrial genomes. Finally, co-stimulation of glutamatergic pathways induced non-linear Ca2+-signaling integration, revealing integrative properties of NAc astrocytes. All these results demonstrate the existence of specific neuron-astrocyte circuits in the NAc, a critical insight to the understanding of how the NAc integrates information.

Neuro-molecular characterization of fish cleaning interactions

Coral reef fish exhibit a large variety of behaviours crucial for fitness and survival. The cleaner wrasse Labroides dimidiatus displays cognitive abilities during interspecific interactions by providing services of ectoparasite cleaning, thus serving as a good model to understand the processes of complex social behaviour. However, little is known about the molecular underpinnings of cooperative behaviour between L. dimidiatus and a potential client fish (Acanthurus leucosternon). Therefore, we investigated the molecular mechanisms in three regions of the brain (fore-, mid-, and hindbrain) during the interaction of these fishes. Here we show, using transcriptomics, that most of the transcriptional response in both species was regulated in the hindbrain and forebrain regions and that the interacting behaviour responses of L. dimidiatus involved immediate early gene alteration, dopaminergic and glutamatergic pathways, the expression of neurohormones (such as isotocin) and steroids (e.g. progesterone and estrogen), as well as social decision-making genes. In contrast, in the client, fewer molecular alterations were found, mostly involving pituitary hormone responses. The particular pathways found suggested learning and memory processes in the cleaner wrasse, while the client indicated stress relief and a reduction in aggression.

Cholinergic-Induced Specific Oscillations in the Medial Prefrontal Cortex to Reverse Propofol Anesthesia

General anesthesia is a drug-induced reversible state comprised of altered states of consciousness, amnesia, analgesia, and immobility. The medial frontal cortex (mPFC) has been discovered to modulate the level of consciousness through cholinergic and glutamatergic pathways. The optogenetic tools combined with in vivo electrophysiological recording were used to study the neural oscillatory modulation mechanisms in mPFC underlying the loss of consciousness (LOC) and emergence. We found that optogenetic activation of both cholinergic and glutamatergic neurons in the basal forebrain (BF) reversed the hypnotic effect of propofol and accelerated the emergence from propofol-induced unconsciousness. The cholinergic light-activation during propofol anesthesia increased the power in the β (12–20 Hz) and low γ (20–30 Hz) bands. Conversely, glutamatergic activation increased the power at less specific broad (1–150 Hz) bands. The cholinergic-induced alteration to specific power bands after LOC had opposite effects to that of propofol. These results suggested that the cholinergic system might act on more specific cortical neural circuits related to propofol anesthesia.

Nitric oxide-mediated defensive and antinociceptive responses organised at the anterior hypothalamus of mice are modulated by glutamatergic inputs from area 24b of the cingulate cortex

Background: Previous studies suggested that Cg1 area of the cingulate cortex of rats controls glutamate-mediated fear-induced defensive behaviour and antinociception organised at the posterior hypothalamus. In turn, microinjection of the nitric oxide donor SIN-1 into the anterior hypothalamus of mice produced defensive behaviours and fear-induced antinociception. However, it remains unknown whether Cg1 also modulates the latter mechanisms in mice. Aims: The present study examined the influence of Cg1 on SIN1-evoked fear-induced defensive behaviour and antinociception organised at the anterior hypothalamus of mice. Methods: The fear-like behavioural and antinociceptive responses to the microinjection of SIN-1 (300 nmol) into the anterior hypothalamus were evaluated after the microinjection of either N-methyl-D-aspartic acid receptor agonist (0.1, 1 and 10 nmol) or physiological saline into the cingulate cortex of C57BL/6 male mice. In addition, neurotracing and immunohistochemistry were used to characterise Cg1-anterior hypothalamus glutamatergic pathways. Results: The data showed that activation of Cg1 N-methyl-D-aspartic acid receptors increased escape while reducing freezing and antinociceptive responses to SIN-1 microinjections into the anterior hypothalamus. Anterograde neural tract tracer co-localised with VGLUT2-labelled fibres suggests these responses are mediated by glutamatergic synapses at the anterior hypothalamus. Conclusions: In contrast with previous studies showing that Cg1 facilitates both escape and antinociception to chemical stimulation of the posterior hypothalamus in rats, the present data suggest that Cg1 facilitates escape while inhibiting defensive antinociception produced by the microinjection of SIN-1 in the anterior hypothalamus of mice. Accordingly, Cg1 may have opposite effects on antinociceptive responses organised in the anterior and posterior hypothalamus of mice and rats, respectively.

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors

Anxiety commonly co‐occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL– and not BLA– and vHipp–NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL–NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

On the Origin of Ultraslow Spontaneous Na+ Fluctuations in Neurons of the Neonatal Forebrain

Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex brain-region-specific networks. The previously reported forms include bursts of electrical activity and oscillations in intracellular Ca2+ concentration. Here, we use ratiometric Na+ imaging to demonstrate spontaneous fluctuations in the intracellular Na+ concentration of CA1 pyramidal neurons and astrocytes in tissue slices obtained from the hippocampus of mice at postnatal days 2-4 (P2-4). These occur at very low frequency (~2/h), can last minutes with amplitudes up to several mM, and mostly disappear after the first postnatal week. To further investigate their mechanisms, we model a network consisting of pyramidal neurons and interneurons. Experimentally observed Na+ fluctuations are mimicked when GABAergic inhibition in the simulated network is made depolarizing. Our experiments and computational model show that blocking voltage-gated Na+ channels or GABAergic signaling significantly diminish the neuronal Na+ fluctuations. On the other hand, blocking a variety of other ion channels, receptors, or transporters including glutamatergic pathways, does not have significant effects. Our model also shows that the amplitude and duration of Na+ fluctuations decrease as we increase the strength of glial K+ uptake. Furthermore, neurons with smaller somatic volumes exhibit fluctuations with higher frequency and amplitude. As opposed to this, larger extracellular to intracellular volume ratio observed in neonatal brain exerts a dampening effect. Finally, our model predicts that these periods of spontaneous Na+ influx leave neonatal neuronal networks more vulnerable to seizure-like states when compared to mature brain.