Discharge Activity Of Neurons Research Articles

Electroacupuncture at different intensities inhibits nociceptive discharges of wide dynamic range neurons in spinal dorsal horn of rats.

To observe the effect of electroacupuncture (EA) at different intensities on nociceptive discharges of wide dynamic range (WDR) neurons in the spinal dorsal horns (DHs) of rats, so as to explore its regulatory characteristics on nociceptive signals at the spinal level. A total of 25 male SD rats were used in the present study. A microelectrode array was used to record the discharge activity of WDR neurons in the lumbar spinal DHs of normal rats. After finding the WDR neuron, electrical stimulation (pulse width of 2 ms) was administered to the plantar receptive field (RF) for determining its response component of discharges according to the latency of action potential generation (Aβ ［0 to 20 ms］, Aδ ［20 to 90 ms］, C ［90 to 500 ms］ and post-discharge ［500 to 800 ms］). High-intensity electrical stimulation was continuously applied to the RF at the paw's plantar surface to induce DHs neuronal windup response. Subsequently, EA stimulation at different intensities (1 mA and 2 mA) was applied to the left "Zusanli"(ST36) at a frequency of 2 Hz/15 Hz for 10 min. The induction of WDR neuronal windup was then repeated under the same conditions. The quantity of nociceptive discharge components and the windup response of WDR neurons before and after EA stimulations at different intensities were compared. Compared to pre-EA, both EA1 mA and EA2 mA significantly reduced the number of Aδ and C component discharges of WDR neurons during stimulation, as well as post-discharge (P<0.01, P<0.001). The inhibitory rate of C component by EA2 mA was significantly higher than that by EA1 mA (P<0.05). Meanwhile, both EA1 mA and EA2 mA attenuated the windup response of WDR neurons (P<0.05, P<0.01), and the effect of EA2 mA was stronger than that of EA1 mA (P<0.05). Further analysis showed that when EA1 mA and EA2 mA respectively applied to both non-receptive field (non-RF) and RF, a significant reduction in the number of Aδ component, C component and post-discharge was observed (P<0.05, P<0.01). EA2 mA at the non-RF and RF demonstrated a significant inhibitory effect on the windup response of WDR neurons (P<0.01, P<0.05), but EA1 mA only at the non-RF showed a significant inhibitory effect on the windup response (P<0.01). EA can suppress nociceptive discharges of spinal DHs WDR neurons in rats. The inhibitory impact of EA is strongly correlated with the location and intensity of EA stimulation, and EA2 mA has a stronger inhibitory effect than EA1 mA.

Simultaneous recording of neuronal discharge and calcium activity reveals claustrum-cortex neurosynchrony under anesthesia

Neural information transmission between deep brain nuclei and the cortex is essential for brain function. Currently, high-resolution simultaneous detection of neural information between the deep brain nuclei and the large-scale cortex still poses challenges. We have developed the microelectrode arrays based on the Micro-Electro-Mechanical System (MEMS) technology, and modified the electrode surface with nanomaterials to improve the electrode performance. This study combined microelectrode arrays and extended-field-of-view microscopy to achieve simultaneous recording of claustrum (CLA) electrophysiology and wide-field cortical calcium imaging at single-cell resolution. This work investigated the synchronous changes of neural information in CLA and cortex of mice during the whole process from wakefulness to anesthesia and then to wakefulness, and summarized the characteristics of the CLA electrophysiology and cortical calcium signaling under different inhalation anesthesia concentrations. We found the synergy between microscopic spike and local field potential (LFP) of CLA neurons under deep anesthesia, and the law that high inhalation anesthesia concentration enhanced the synchronization between neurons in CLA and cortex. The combination of microelectrode arrays and extended-field-of-view microscopy also gives a new method for synchronous detection of multimodal and multi-brain region neural information.

Transforming growth factor-beta 1 enhances discharge activity of cortical neurons.

JOURNAL/nrgr/04.03/01300535-202502000-00031/figure1/v/2024-05-28T214302Z/r/image-tiff Transforming growth factor-beta 1 (TGF-β1) has been extensively studied for its pleiotropic effects on central nervous system diseases. The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved. Voltage-gated sodium channels (VGSCs) are essential ion channels for the generation of action potentials in neurons, and are involved in various neuroexcitation-related diseases. However, the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear. In this study, we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice. We found that TGF-β1 increased VGSC current density in a dose- and time-dependent manner, which was attributable to the upregulation of Nav1.3 expression. Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase (PD98059), p38 mitogen-activated protein kinase (SB203580), and Jun NH2-terminal kinase 1/2 inhibitor (SP600125). Interestingly, TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons. These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway, which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions. Thus, this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.

The hyperthermic response to intra-preoptic area administration of agmatine in male rats

Agmatine is an endogenous biogenic amine that exerts various effects on the central nervous system. The hypothalamic preoptic area (POA, thermoregulatory command center) has high agmatine immunoreactivity. In this study, in conscious and anesthetized male rats, agmatine microinjection into the POA induced hyperthermic responses associated with increased heat production and locomotor activity. Intra-POA administration of agmatine increased the locomotor activity, the brown adipose tissue temperature and rectum temperature, and induced shivering as demonstrated by increased neck muscle electromyographic activity. However, intra-POA administration of agmatine almost had no impact on the tail temperature of anesthetized rats. Furthermore, there were regional differences in the response to agmatine in the POA. The most effective sites for the microinjection of agmatine to elicit hyperthermic responses were localized in the medial preoptic area (MPA). Agmatine microinjection into the median preoptic nucleus (MnPO) and lateral preoptic nucleus (LPO) had a minimal effect on the mean core temperature. Analysis of the in vitro discharge activity of POA neurons in brain slices when perfused with agmatine showed that agmatine inhibited most warm-sensitive but not temperature-insensitive neurons in the MPA. However, regardless of thermosensitivity, the majority of MnPO and LPO neurons were not responsive to agmatine. The results demonstrated that agmatine injection into the POA of male rats, especially the MPA, induced hyperthermic responses, which may be associated with increased BAT thermogenesis, shivering and locomotor activity by inhibiting warm-sensitive neurons.

Alterations in the intrinsic discharge activity of CA1 pyramidal neurons associated with possible changes in the NADPH diaphorase activity in a rat model of autism induced by prenatal exposure to valproic acid

Autism spectrum disorder is a neurodevelopmental disorder characterized by sensory abnormalities, social skills impairment and cognitive deficits. Although recent evidence indicated that induction of autism-like behavior in animal models causes abnormal neuronal excitability, the impact of autism on neuronal properties is still an important issue. Thus, new findings at the cellular level may shed light on the pathophysiology of autism and may help to find effective treatment strategies. Here, we investigated the behavioral, electrophysiological and histochemical impacts of prenatal exposure to valproic acid (VPA) in rats. Findings revealed that VPA exposure caused a significant increase in the hot plate response latency. The novel object recognition ability was also impaired in VPA-exposed rats. Along with these behavioral alterations, neurons from VPA-exposed animals exhibited altered excitability features in response to depolarizing current injections relative to control neurons. In the VPA-exposed group, these changes consisted of a significant increase in the amplitude, evoked firing frequency and the steady-state standard deviation of spike timing of action potentials (APs). Moreover, the half-width, the AHP amplitude and the decay time constant of APs were significantly decreased in this group. These changes in the evoked electrophysiological properties were accompanied by intrinsic hyperexcitability and lower spike-frequency adaptation and also a significant increase in the number of NADPH-diaphorase stained neurons in the hippocampal CA1 area of the VPA-exposed rats. Taken together, findings demonstrate that abnormal nociception and recognition memory is associated with alterations in the neuronal responsiveness and nitrergic system in a rat model of autism-like.

The functional operation of the vestibulo-ocular reflex.

The biophysical properties of the labyrinthine semicircular canals, and the electrophysiological properties of peripheral vestibular afferent neurons over a range of stimulus frequencies, are reviewed. Resting discharge activity and adaptive properties of vestibular neurons are discussed. Central processing of vestibular signals is then examined, including push-pull organization and the velocity storage mechanism. A detailed treatment of the final common neural integrator for oculomotor signals follows with consideration of its neural substrate and how distributed networks of neurons can overcome several problems posed by conventional control-systems models, such as why neural signals, but not background discharge, are integrated. Next, the behavior of the vestibulo-ocular reflex in darkness is compared with how it satisfies visual demands during natural activities. Finally, the reflex's performance at high frequencies of head rotation is discussed.

Neuronal discharge activity in mouse medial prefrontal cortex during associative motor learning

Neuronal discharge activity in mouse medial prefrontal cortex during associative motor learning

Dynamic response of the e-HR neuron model under electromagnetic induction

Due to the fluctuation of membrane potential of neuron, there are complex time-varying electromagnetic fields in nervous systems, and the exciting electromagnetic field will further regulate the discharge activities of neurons. In this paper, the coupling of magnetic flux variables to the membrane potential is realised by using a magnetron memristor, and then a 5D extended Hindmarsh–Rose (e-HR) neuron model is established. With the help of Matcont software, the distribution and bifurcation properties of the equilibrium point in the e-HR model is analysed. It is found that there are subcritical Hopf bifurcation, coexisting oscillation modes and hidden limit cycle attractors with period 1 and period 2. In addition, by applying the washout controller, the subcritical Hopf bifurcation point can be transformed into the supercritical Hopf bifurcation point. Thus, the hidden oscillation behaviour of the model can be effectively eliminated. In order to analyse the influence of various parameters on the bifurcation behaviour, numerical simulation of two-parameter bifurcation, single-parameter bifurcation, maximum Lyapunov exponential and time response are given. It is found that the e-HR neuron has a complex bifurcation structure, i.e., the bifurcation structure with period-doubling bifurcations, inverse period-doubling bifurcations, period-adding bifurcations with and without chaos. At the same time, the study also finds that the coexistence behaviour of the periodic cluster discharge and the mixed-mode oscillations (MMOs) can be observed from the bifurcation structure with unique ‘periodic dislocation layer’ on the two-parameter plane. Interestingly, the bursting mode of the system is converted into MMOs when the system parameters are randomly perturbed. The results of this study provide useful insights into the complex discharge patterns and hidden discharge behaviours of neurons under electromagnetic induction.

Early life maternal deprivation attenuates morphine induced inhibition in lateral paragigantocellularis neurons in adult rats

Early life stress can serve as one of the principle sources leading to individual differences in confronting challenges throughout the lifetime. Maternal deprivation (MD), a model of early life stress, can cause persistent alterations in brain function, and it may constitute a risk factor for later incidence of drug addiction. It is becoming more apparent that early life MD predisposes opiate abuse in adulthood. Although several behavioral and molecular studies have addressed this issue, changes in electrophysiological features of the neurons are yet to be understood. The lateral paragigantocellularis (LPGi) nucleus, which participates in the mediation of opiate dependence and withdrawal, may be susceptible to modifications following MD. This study sought to find whether early life MD can alter the discharge activity of LPGi neurons and their response to acute morphine administration in adult rats.Male Wistar rats experienced MD on postnatal days (PNDs) 1–14 for three h per day. Afterward, they were left undisturbed until PND 70, during which the extracellular activities of LPGi neurons were recorded in anesthetized animals at baseline and in response to acute morphine.In both MD and control groups, acute morphine administration induced heterogeneous (excitatory, inhibitory, and no effect) responses in LPGi neurons. At baseline recording, the interspike interval variability of the LPGi neurons was attenuated in both inhibitory and excitatory responses in animals with the history of MD. The extent of morphine-induced discharge inhibition was also lower in deprived animals compared to the control group.These findings suggest that early life MD induces long-term alterations in LPGi neuronal activity in response to acute administration of morphine. Therefore, the MD may alter the vulnerability to develop opiate abuse in adulthood.

Dynamic response and control of neuros based on electromagnetic field theory

The time-varying electric fields generated by continuously pumping and transmitting calcium, potassium and sodium ions in cells not only affect the discharge activity of neurons, but also induce time-varying magnetic fields to further regulate the fluctuation of ions. According to the Maxwell's electromagnetic field theory, time-varying electric field and magnetic field can stimulate each other in the electrophysiological environment inside and outside the cells to produce electromagnetic field. In order to explore the discharge rhythm transition of neurons under the influence of electromagnetic fields, a five-dimensional (5D) HR neuron model (EMFN model for short) is established by introducing magnetic flux variable and electric field variable into a three-dimensional (3D) Hindmarsh-Rose (HR) neuron model. Firstly, the equilibrium distribution and global bifurcation properties of EMFN model are analyzed by Matcont software, then the existence of subcritical Hopf bifurcation, hidden discharge, coexistence of periodic discharge and resting state are found and analyzed. Secondly, by using the tools of two-parameter and one-parameter bifurcation, ISI bifurcation and the maximum Lyapunov exponent for numerical simulation, the period-adding bifurcation with and without chaos, mixed mode discharge and coexistence mode discharge in the EMFN model are analyzed in detail. At the same time, the transition law of discharge rhythm with the influence of electric field and magnetic field intensity is revealed. Finally, the Washout controller is used to convert the subcritical Hopf bifurcation into supercritical Hopf bifurcation, so the topological structure of EMFN model near the bifurcation point is changed for eliminating the hidden discharge. The research results of this paper confirm that the novel neuron model has rich discharge rhythm, which will affect the information transmission and coding, and provide some ideas for improving the neuron models, revealing the influence of electromagnetic field on biological nervous system, and exploring the pathogenic mechanism of some neurological diseases.

Pacemaking Activity in the Peripheral Nervous System: Physiology and Roles of Hyperpolarization Activated and Cyclic Nucleotide-Gated Channels in Neuropathic Pain.

The most famous pacemaking activity found in the human body is in the cardiac system. However, pacemaking is also widely present in the nervous system. The ion channels responsible for the pacemaking activity are called hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. HCN channels are activated during hyperpolarization and create an inward current named Ih containing mixed sodium and potassium ions. The molecular mechanism of these unique features remains mysterious. In the peripheral nervous system (PNS), pacemaking is unique because it is only present in pathologic states when nerve damage occurs and leads to neuropathic pain. For this reason, pacemaking in neuropathic pain is also known as ectopic discharge. In our literature review, the HCN channel physiology is one of the research interests. We will present studies exploring the molecular mechanisms involved in HCN gating and ion permeability. The second research question is, what makes the pacemaking activity unique in the PNS? Thus, our paper will include studies that discuss the role of HCN channels in neuropathic pain. Given the fundamental role of HCN channels in regulating neuronal cells' discharge activity, the modulation of their function for therapeutic purposes could be useful in various pathological conditions. Here we review the present knowledge of the efficacy of HCN blocker treating neuropathic pain in humans.

Effect of mild traumatic brain injury on spontaneous activity of rat primary somatosensory cortex and its responsivity to vibrotactile stimulation

While it has been previously demonstrated that concussion severity can be assessed using sensory tests of cortical functionality, the underlying neural mechanisms affected by concussion are still poorly understood. By using an animal model, it is possible to directly observe the neurophysiological effects of concussion, and thus shed light on the underlying changes in cortical functionality. In order to assess the effects of a single concussion, we recorded spike discharge activity of neurons in the rat primary somatosensory cortex prior to as well as 6-12hr and 78-86hr after a mild weight-drop impact-acceleration closed-head trauma. During the 6-12hr post-impact period, cortical spontaneous activity was elevated by 40% compared to the healthy control state, but its responsivity to vibrotactile stimulation was not significantly affected. However, the responsivity to vibrotactile stimulation did decline in the 78-86hr post-impact period. Also during this period, spontaneous activity in the middle and upper cortical layers was reduced by 35% below the healthy control state, but it remained high in the deep layers. We also recorded somatosensory cortical activity 6-12hr after delivering a second head trauma, identical to the one delivered 72hr prior. Although the two impacts mechanically were the same, the neurophysiological effect of the second impact was very different from that observed after the first impact: both the stimulus-evoked response and spontaneous activity were significantly reduced as compared to the same time period after the first impact. These findings demonstrate that mTBI alters the functional state of the somatosensory cortex in a post-injury time-dependent manner.

Maternal deprivation induces persistent adaptations in putative dopamine neurons in rat ventral tegmental area: in vivo electrophysiological study.

Early life aversive experiences can trigger persistent deficits in neuronal signaling within the mesolimbic pathway, most notably in the dopamine (DA) neurons of the ventral tegmental area (VTA). The identity of such cellular mechanisms currently appears as an important issue. To address this concern, we investigated whether early life maternal deprivation (MD) would affect the electrical activity of VTA DA neurons, via in vivo extracellular single-unit recording. Male Wistar rats were deprived of their dams for 3h per day from postnatal days (PND) 1-14. Thereafter, the adult animals (PND 70-80) were tested for the discharge activity of putative VTA DA neurons. The VTA DA neurons displayed a decrease in firing rate and an increase in the variability of baseline discharge activity in deprived animals. MD also caused a decrease in burst firing of VTA DA neurons compared to control subjects. In summary, early life MD induces a hypoactive VTA DA system, which may contribute to lifespan psychopathologies.

The orexinergic neural pathway from the lateral hypothalamus to the nucleus accumbens and its regulation of palatable food intake

ObjectiveTo explore the orexinergic pathway from the lateral hypothalamus (LHA) to the nucleus accumbens (NAc) and its regulation on the palatable food intake. MethodsFluorescent gold retrograde tracing combined with fluoro-immunohistochemical staining were used to observe the projection of orexinergic neurons from LHA to NAc. The orexin-A expression in LHA and c-Fos in NAc were studied after electrical stimulation of LHA. The firing rates of neurons were monitored by single-unit extracellular electric discharge recording and the palatable food intake were measured after orexin microinjection in NAc or electrical stimulation of LHA. Results(1) Fluorescent gold retrograde tracing combined with fluoro-immunohistochemical staining showed some orexinergic neural projection from the LHA to the NAc shell. (2) Electrical stimulation of LHA significantly enhanced the expression of orexin-A in LHA and the expression of c-Fos in NAc (P < .05). (3) The results of single-unit extracellular discharge recording showed that the microinjection of orexin in NAc or electrical stimulation of LHA significantly increased the discharge activity of gastric distension responsive neurons in NAc, and the effect could be partly blocked by pretreatment of orexin-A receptor inhibitor SB334867 in NAc (P < .05). (4) Microinjection orexin-A in NAc or electrical stimulation of LHA significantly increased the palatable food intake in rats, and the effect also was partly inhibited by pretreatment of SB334867 in NAc (P < .05). ConclusionThere is an orexinergic pathway from LHA to NAc, which may have potential regulatory effects on food reward and obesity.

Effects of Cholinergic Neuromodulation on Thalamocortical Rhythms During NREM Sleep: A Model Study.

It has been suggested that cholinergic neurons shape the oscillatory activity of the thalamocortical (TC) network in behavioral and electrophysiological experiments. However, theoretical modeling demonstrating how cholinergic neuromodulation of thalamocortical rhythms during non-rapid eye movement (NREM) sleep might occur has been lacking. In this paper, we first develop a novel computational model (TC-ACH) by incorporating a cholinergic neuron population (CH) into the classical thalamo-cortical circuitry, where connections between populations are modeled in accordance with existing knowledge. The neurotransmitter acetylcholine (ACH) released by neurons in CH, which is able to change the discharge activity of thalamocortical neurons, is the primary focus of our work. Simulation results with our TC-ACH model reveal that the cholinergic projection activity is a key factor in modulating oscillation patterns in three ways: (1) transitions between different patterns of thalamocortical oscillations are dramatically modulated through diverse projection pathways; (2) the model expresses a stable spindle oscillation state with certain parameter settings for the cholinergic projection from CH to thalamus, and more spindles appear when the strength of cholinergic input from CH to thalamocortical neurons increases; (3) the duration of oscillation patterns during NREM sleep including K-complexes, spindles, and slow oscillations is longer when cholinergic input from CH to thalamocortical neurons becomes stronger. Our modeling results provide insights into the mechanisms by which the sleep state is controlled, and provide a theoretical basis for future experimental and clinical studies.

Regulation of Chemical Autapse on an FHN-ML Neuronal System

To explore the feasibility of physiological manipulation of autaptic structures, the effects of autaptic connections on an FHN-ML neuronal system with phase noise stimulation are studied systematically. Firstly, according to the dynamic analysis of the FHN-ML neuron model, a saddle-node bifurcation can occur on an invariant circle. Under the action of external oscillatory current with phase noise, the neuronal firing activity is sensitive to phase noise with less intensity, and an appropriate noise intensity can induce a significant stochastic resonance phenomenon. Secondly, the chemical autaptic function can effectively regulate the neuronal discharge activity. An inhibitory autapse can not only induce the transition from depolarized resting to periodic spiking, but can also induce the FHN-ML neuron suppressed by strong phase noise to generate a pronounced intermittent high-level burst-like discharge mode when the autaptic conductance is greater than 0.1. Finally, for a two-dimensional regular FHN-ML neuronal network, a small amount of autaptic structures can induce some special waveforms to restore the propagation of nerve impulses interrupted by phase noise disturbance. This indicates the significant regulation of autapses on spatial patterns of the FHN-ML neuronal network. The study can provide some theoretical guidance for building autaptic structures in local areas to modulate the dynamic behaviors of biological neuronal systems.

Mechanical stimulation of cervical vertebrae modulates the discharge activity of ventral tegmental area neurons and dopamine release in the nucleus accumbens

BackgroundGrowing evidence suggests that mechanical stimulation modulates substrates in the supraspinal central nervous system (CNS) outside the canonical somatosensory circuits.Objective/Methods: We evaluate mechanical stimulation applied to the cervical spine at the C7-T1 level (termed “MStim”) on neurons and neurotransmitter release in the mesolimbic dopamine (DA) system, an area implicated in reward and motivation, utilizing electrophysiological, pharmacological, neurochemical and immunohistochemical techniques in Wistar rats. ResultsLow frequency (45–80 Hz), but not higher frequency (115 Hz), MStim inhibited the firing rate of ventral tegmental area (VTA) GABA neurons (52.8% baseline; 450 s) while increasing the firing rate of VTA DA neurons (248% baseline; 500 s). Inactivation of the nucleus accumbens (NAc), or systemic or in situ antagonism of delta opioid receptors (DORs), blocked MStim inhibition of VTA GABA neuron firing rate. MStim enhanced both basal (178.4% peak increase at 60 min) and evoked DA release in NAc (135.0% peak increase at 40 min), which was blocked by antagonism of DORs or acetylcholine release in the NAc. MStim enhanced c-FOS expression in the NAc, but inhibited total expression in the VTA, and induced translocation of DORs to neuronal membranes in the NAc. ConclusionThese findings demonstrate that MStim modulates neuron firing and DA release in the mesolimbic DA system through endogenous opioids and acetylcholine in the NAc. These findings demonstrate the need to explore more broadly the extra-somatosensory effects of peripheral mechanoreceptor activation and the specific role for mechanoreceptor-based therapies in the treatment of substance abuse.

Electrical Mode Transition of Hybrid Neuronal Model Induced by External Stimulus and Electromagnetic Induction

Based on a hybrid neuronal model of the Hindmarsh–Rose (HR) model (the slow negative feedback dynamics) with the Wilson model (the fast variable dynamics), the discharge modes of neurons are studied by using bifurcation analysis. When the hybrid neuronal model is driven by external stimulus current, the hybrid neuronal model is capable of simulating an extensive range of bursting patterns with different systemic parameters. With the increase of external stimulus, the multiple discharge patterns of neurons arise, and the electrical modes of the neurons appear for successive transitions. When the hybrid neuronal model is driven by electromagnetic induction, the electrical activities of the neurons have different responses to the variations in the amplitude and the angular frequency of high and low frequency electromagnetic radiations. It is found that the neuronal discharge activity is transformed from chaotic state to periodic state by increasing the angular frequency, and the firing pattern of neuron can be shifted from the bursting state to chaotic state by increasing the amplitude of the low frequency signal.

Genetic approaches to the investigation of serotonergic neuron functions in animals

The serotonergic system is one of the most important neurotransmitter systems that take part in the regulation of vital CNS functions. The understanding of its mechanisms will help scientists create new therapeutic approaches to the treatment of mental and neurodegenerative diseases and find out how this neurotransmitter system interacts with other parts of the brain and regulates their activity. Since the serotonergic system anatomy and functionality are heterogeneous and complex, the best tools for studying them are based on manipulation of individual types of neurons without affecting neurons of other neurotransmitter systems. The selective cell control is possible due to the genetic determinism of their functions. Proteins that determine the uniqueness of the cell type are expressed under the regulation of cell-specific promoters. By using promoters that are specific for genes of the serotonin system, one can control the expression of a gene of interest in serotonergic neurons. Here we review approaches based on such promoters. The genetic models to be discussed in the article have already shed the light on the role of the serotonergic system in modulating behavior and processing sensory information. In particular, genetic knockouts of serotonin genes sert, pet1, and tph2 promoted the determination of their contribution to the development and functioning of the brain. In addition, the review describes inducible models that allow gene expression to be controlled at various developmental stages. Finally, the application of these genetic approaches in optogenetics and chemogenetics provided a new resource for studying the functions, discharge activity, and signal transduction of serotonergic neurons. Nevertheless, the advantages and limitations of the discussed genetic approaches should be taken into consideration in the course of creating models of pathological conditions and developing pharmacological treatments for their correction.

HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature

The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the Ih current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of Ih can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels’ activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by Ih dysfunction in the pathogenesis of epilepsy.