Deep learning models for atypical serotonergic cells recognition.

Background: The serotonergic system modulates brain processes via functionally distinct subpopulations of neurons with heterogeneous properties, including their electrophysiological activity. In extracellular recordings, serotonergic neurons to be investigated for their functional properties are commonly identified on the basis of "typical" features of their activity, i.e.

Antidepressant-induced increase in GluA2 expression does not translate in changes of AMPA receptor-mediated synaptic transmission at CA3/CA1 synapses in rats.

Chronic treatment with serotonin selective reuptake inhibitors or tryciclic antidepressant drugs in rodents has been shown to increase the expression of GluA1 and/or GluA2 AMPA receptor (AMPAR) subunits in several brain areas, including the hippocampus. These changes in AMPAR composition have been suggested to result in increased glutamatergic neurotransmission and possibly underlie enhanced hippocampal synaptic plasticity through the increased availability of calcium-permeable AMPARs, specifically at CA3/CA1 synapses. However, the possibility that chronic treatment with antidepressants actually results in strengthened glutamatergic neurotransmission in CA1 has poorly been investigated.

Pharmacovigilance and Pharmacoepidemiology as a Guarantee of Patient Safety: The Role of the Clinical Pharmacologist.

Recent years, particularly the COVID-19 pandemic, can be considered a turning point for pharmacovigilance and pharmacoepidemiology in terms of their role in drug safety and drug utilisation monitoring in clinical practice [...

Therapeutic Potential of Highly Selective A Adenosine Receptor Ligands in the Central and Peripheral Nervous System.

Ligands of the G protein-coupled adenosine A receptor (AR) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe pharmacological profiles emerging from clinical trials on different pathologies (e.g.

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner.

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine () and their wild type () congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress.

Acetylcholine modulates K and Na currents in human basal forebrain cholinergic neuroblasts through an autocrine/paracrine mechanism.

The Nucleus Basalis of Meynert (NBM) is the main source of cholinergic neurons in the basal forebrain to be crucially involved in cognitive functions and whose degeneration correlates with cognitive decline in major degenerative pathologies as Alzheimer's and Parkinson's diseases. However, knowledge concerning NBM neurons derived from human brain is very limited to date. We recently characterized a primary culture of proliferating neuroblasts isolated from the human fetal NBM (hfNBM) as immature cholinergic neurons expressing the machinery to synthetize and release acetylcholine.

Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism.

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations.

Serotonin Deficiency Increases Context-Dependent Fear Learning Through Modulation of Hippocampal Activity.

Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 () knockout mice.

Differential modulation of CA1 impulse flow by endogenous serotonin along the hippocampal longitudinal axis.

The hippocampus is functionally differentiated along its longitudinal axis, with the dorsal and ventral segments preferentially involved in cognitive and emotional processing, respectively. Serotonergic modulation of hippocampal function has been extensively studied, but its relation to the dorsoventral axis has remained largely unknown. To examine the modulation of hippocampal output along the dorsoventral axis by endogenous serotonin (5-HT) we compared the effect of the 5-HT/noradrenaline (NA)-releaser, 3,4-methylenedioxymethamphetamine (MDMA), in transversal slices encompassing the entire rat hippocampus.

Increased functional coupling of 5-HT autoreceptors to GIRK channels in Tph2 mice.

Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT autoreceptors (5-HTARs). Enhanced 5-HTAR functioning may cause decreased serotonergic signaling in brain and has thereby been implicated in the etiology of mood and anxiety disorders. Tryptophan hydroxylase-2 knockout (Tph2) mice exhibit sensitization of 5-HT agonist-induced inhibition of serotonergic neuron firing and thus represents a unique animal model of enhanced 5-HTAR functioning.

Direct imaging of APP proteolysis in living cells.

Alzheimer's disease is a multifactorial disorder caused by the interaction of genetic, epigenetic and environmental factors. The formation of cytotoxic oligomers consisting of A peptide is widely accepted as being one of the main key events triggering the development of Alzheimer's disease. A peptide production results from the specific proteolytic processing of the amyloid precursor protein (APP).

Firing Properties of Genetically Identified Dorsal Raphe Serotonergic Neurons in Brain Slices.

Tonic spiking of serotonergic neurons establishes serotonin levels in the brain. Since the first observations, slow regular spiking has been considered as a defining feature of serotonergic neurons. Recent studies, however, have revealed the heterogeneity of serotonergic neurons at multiple levels, comprising their electrophysiological properties, suggesting the existence of functionally distinct cellular subpopulations.

Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice.

Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications.

Purinergic signalling in brain ischemia.

Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia a primary damage due to the early massive increase of extracellular glutamate is followed by activation of resident immune cells, i.e microglia, and production or activation of inflammation mediators.

Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe 5-HT Neurons.

G protein-activated inwardly rectifying potassium (GIRK) channels in 5-HT neurons are assumed to be principal effectors of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, but their pharmacology, subunit composition and the role in regulation of 5-HT neuron activity have not been fully elucidated. We sought for a pharmacological tool for assessing the functional role of GIRK channels in 5-HT neurons by characterizing the effects of drugs known to block GIRK channels in the submicromolar range of concentrations. Whole-cell voltage-clamp recording in brainstem slices were used to determine concentration-response relationships for the selected GIRK channel blockers on 5-HT1A autoreceptor-activated inwardly rectifying K+ conductance in rat dorsal raphe 5-HT neurons.

Cellular resilience: 5-HT neurons in Tph2(-/-) mice retain normal firing behavior despite the lack of brain 5-HT.

Considerable evidence links dysfunction of serotonin (5-hydroxytryptamine, 5-HT) transmission to neurodevelopmental and psychiatric disorders characterized by compromised "social" cognition and emotion regulation. It is well established that the brain 5-HT system is under autoregulatory control by its principal transmitter 5-HT via its effects on activity and expression of 5-HT system-related proteins. To examine whether 5-HT itself also has a crucial role in the acquisition and maintenance of characteristic rhythmic firing of 5-HT neurons, we compared their intrinsic electrophysiological properties in mice lacking brain 5-HT, i.

Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity.

The firing activity of serotonergic neurons in raphe nuclei is regulated by negative feedback exerted by extracellular serotonin (5-HT)o acting through somatodendritic 5-HT1A autoreceptors. The steady-state [5-HT]o, sensed by 5-HT1A autoreceptors, is determined by the balance between the rates of 5-HT release and reuptake. Although it is well established that reuptake of 5-HTo is mediated by 5-HT transporters (SERT), the release mechanism has remained unclear.

Endogenous serotonin facilitates hippocampal long-term potentiation at CA3/CA1 synapses.

Encoding of episodic memory requires long-term potentiation (LTP) of neurotransmission at excitatory synapses of the hippocampal circuitry. Previous data obtained with the application of exogenous 5-hydroxytryptamine (5-HT) in hippocampal slices indicate that 5-HT blocks LTP, which contrasts with the facilitatory effect of selective serotonin reuptake inhibitors (SSRIs) on learning and memory observed in vivo. Here, we investigated the effects of endogenous 5-HT, released from terminals by the monoamine releaser 3,4-methylenedioxymethamphetamine (MDMA), on LTP of field EPSPs induced by theta-burst stimulation and recorded at CA3/CA1 synapses of rat hippocampal slices.

Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis.

Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice.

Suppression of serotonin neuron firing increases aggression in mice.

Numerous studies link decreased serotonin metabolites with increased impulsive and aggressive traits. However, although pharmacological depletion of serotonin is associated with increased aggression, interventions aimed at directly decreasing serotonin neuron activity have supported the opposite association. Furthermore, it is not clear if altered serotonin activity during development may contribute to some of the observed associations.

Impaired chemosensitivity of mouse dorsal raphe serotonergic neurons overexpressing serotonin 1A (Htr1a) receptors.

Background: Serotonergic system participates in a wide range of physiological processes and behaviors, but its role is generally considered as modulatory and noncrucial, especially concerning life-sustaining functions. We recently created a transgenic mouse line in which a functional deficit in serotonin homeostasis due to excessive serotonin autoinhibition was produced by inducing serotonin 1A receptor (Htr1a) overexpression selectively in serotonergic neurons (Htr1a raphe-overexpressing or Htr1a(RO) mice). Htr1a(RO) mice exhibit episodes of autonomic dysregulation, cardiovascular crises and death, resembling those of sudden infant death syndrome (SIDS) and revealing a life-supporting role of serotonergic system in autonomic control.

Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.

Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2).

Consensus document on European brain research.

Psychiatric and neurological diseases combined represent a considerable social and economic burden in Europe. A recent study conducted by the European Brain Council (EBC) quantified the 'cost and burden' of major brain diseases in Europe, amounting to €386bn per year. Considering that these costs will increase exponentially in the years to come due to ageing of the European population, it is necessary to act now in order to curb this increase and possibly reverse the trend.

Enhanced hippocampal long-term potentiation following repeated MDMA treatment in Dark-Agouti rats.

In rats and primates, (±)3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces both long-lasting damage to serotonergic axons and memory impairment. Our objective was to determine effects of neurotoxic dose of MDMA on long-term potentiation (LTP) in hippocampal area CA1 in Dark-Agouti (DA) rats. One week after neurotoxic MDMA treatment in vivo (12.