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The vestibular system includes different anatomical structures and physiological pathways. In the first part of this chapter, we will briefly introduce the main anatomical constituents, i.e., vestibule, semicircular canals, vestibular ganglia and nerve, vestibular nuclei, flocculo-nodular lobe of cerebellum and other structures in the brain stem. In the second parts, we will discuss the pathways generated by signals transduced by vestibular structures. Briefly, the bony labyrinth is lined with the endolymph-containing membranous labyrinth, showing two chambers (utricle and saccule) and three semicircular canals (horizontal, anterior, and posterior). Each canal contains a receptor organ called crista ampullaris, whereas receptor organs of both utriculus and sacculus are called otolithic macula. All the information transduced by receptors travels through the vestibular nerve fibers and reachs the vestibular nuclei in the pons and medulla oblongata. The axons originated here supply various CNS areas, e.g., the spinal cord, oculogyric nuclei, the reticular formation, and the cerebellum. Vestibular receptors respond to accelerations of the head in space, providing direct information about its rotations (receptors of semicircular canals), orientation with respect to gravity and linear movements (receptors of otolithic maculae). Semicircular canals are excited by rotational accelerations, converted into rotational velocity signals by the mechanical structure of the canal. Each labyrinth is excited by ipsilateral head rotation, both labyrinths are excited by purely forward or backward rotation. The utricular macula lies horizontally, whereas the saccular macula is placed vertically. When the head is still and held erect with respect to gravity, the utricular macula is not stimulated, and tilts from the erect posture will excite utricular afferents. Conversely, the saccular macula is strongly stimulated when the head is erect, and little or not when the head is lying on either side. Vestibular signals (ipsilateral rotational head velocity, head tilt, or equivalent linear acceleration) assist balance: the vestibulocervical reflex excites neck muscles via the medial vestibulospinal tract to oppose head tilt, and vestibulospinal reflexes excite ipsilateral limb extensors via the lateral vestibulospinal tract to oppose body tilt.

Temporal lobe epilepsy (TLE) is the most common type of partial complex seizure in adulthood [1]. Within the framework of hyperexcitability, growing interest has risen on the impact of cannabinoids on the control of paroxysmal phenomena [2], despite their reputation as psychotropic substances with addictive properties [3; 4]. In this regard, it was reported that the on-demand production of endocannabinoids from over-activated postsynaptic cells inhibits neurotransmitter release, hence protecting against excitotoxicity in the hippocampus [5; 6]. Nonetheless, the potential anticonvulsant action of cannabinoids has not been fully addressed. Indeed, CB-mediated effects in animal models are attributed not only to the functional involvement of the classical CB receptors-dependent signalling [7; 8], but also to the interaction with further synaptic processes concerning modulatory messengers. Among these, nitric oxide (NO) has caught our attention since it apparently acts as a mediator for cannabinoid effects [9; 10]. In the current study, we focused on two distinct rat models of TLE, the Maximal Dentate Activation and the Pilocarpine-induced acute seizures, providing electrophysiological and behavioural data on cannabinoid and nitrergic system interplay. We evaluated the antiepileptic effects of WIN 55,212-2 (WIN), a CB agonist, and of 7-Nitroindazole (7NI), a preferential inhibitor of neuronal NO synthase (nNOS), at different doses, alone and in combination. MDA study showed that these drugs protected animals from electrically-induced epileptiform discharges. In pilocarpine model, a dose-related activity of 7NI and WIN: a) decreased the behavioural scoring, used to describe the severity of chemically-induced acute seizures; b) affected latency of the onset of acute convulsions; c) dampened mortality rate. Interestingly, the combination of the treatments brought to light that individually ineffective doses of WIN turn into effective when nNOS activity is pharmacologically inhibited in both experimental conditions. Further MDA studies were conducted with a view to explore the pathway downstream NO. To achieve this, we modulated the activity of NO-dependent soluble Guanylate cyclase (sGC), a cGMP-synthase enzyme, which is the main target of NO signaling. We exploited ODQ, a NO-dependent-sGC inhibitor, to evaluate its effect in co-administration with WIN. Results obtained suggested a possible involvement of cGMP pathway in the crosstalk between CB and NO. Taken all these into consideration, our findings suggest a putative antagonism between CB-activated pathway and NO signalling in the context of neuronal hyperexcitability and contribute to elucidate possible synaptic processes underlying neuroprotective properties of cannabinoids, with a view to better integrate antiepileptic therapy.

Environmental stimuli, occurring early in life, shape the drinking trajectories and the psychopathological outcome of alcohol consumption in adult life. In particular, early perinatal procedures can permanently alter various patterns of drug use and behaviour in rat adulthood (Pryce CR, 2001). Early handling (EH) apparently is responsible for neurochemical and behavioural changes in adulthood, due to boosts in maternal care after daily reunion. It has been suggested that fostered maternal care, in the form of licking and grooming, is a key feature in determining neural changes and offspring fear responses and alter the reward/reinforcement pathway through epigenetic mechanisms that likely underlie remodeling in DA transmission (Francis, 2008, Francis et al., 2002). Such evidence is important, since fear together with stress, is thought to be related to vulnerability associated with drug abuse (Kreek and LaForge, 2007; Sinha and Li, 2007). Various studies on ethanol consumption and preference, showed less vulnerability to ethanol in adult male rats submitted to EH procedure (Ploj K, 2003). Based upon these findings, this study was aimed at examining the impact of brief early handling, 15-minute daily separations of litters from the dams during the first 2 weeks of life, on vulnerability to heavy drinking and dependence in adult male Wistar rats employed an operant self-administration procedure well known as a valid paradigm, highly predictive of drug-seeking and drug-taking behaviour in rats (Higgins et al., 1994). The operant-drinking behaviour protocol consisted of: 1) Training phase in which the animals learnt to self-administer EtOH 10% over 21 days; 2) Extinction phase during which reward delivery was suspended; 3) Deprivation period when ethanol self-administration was suspended for 7 days to achieve a forced abstinence; 4) Relapse phase, 7 days, to assess animal reinstatement for ethanol (Cacace, 2012). Our data revealed that EH procedure has a protective influence towards the onset and escalation of drug abuse, showing a reduction in addictive behaviour as displayed by a lower frequency of lever presses with respect to control group. These findings further corroborate the role of early life experiences on ethanol consumption in adulthood, highlighting that environmental influences may induce individual different responses to drug abuse.

Rats self-administer acetaldehyde(ACD), ethanol's first metabolite, directly into cerebral ventricles (1), and multiple ICV infusions of ACD produce conditioned place preference (2). ACD, such as alcohol and other substances of abuse, interacts with dopaminergic reward system (3) and its reinforcing and addictive properties have been assessed through an operant-conflict conditioning procedure (4). Since dopamine D2receptor over-expression in the Nacc attenuates alcohol intake (5), this study aims at exploring the effects of ropinirole administration during abstinence, on ACD relapse. The protocol has been scheduled into 3 different periods: training ( animals have been trained to self-administer ACD solution 3,2%v/v in order to obtain the induction and maintenance of an operant-drinking behavior), deprivation ( rats have undergone repeated 1-week ACD abstinence during and received ropinirole at 0,03 mg/kg/day i.p.); and relapse (rats increase their operant behavior following deprivation). Our results indicate that ropinirole is able to reduce reinstatement of ACD operant-drinking behavior, confirming that hypo-dopaminergic activity is responsible for drug seeking behavior and relapse following abstinence. Further investigation could help considering ropinirole as a therapeutical tool for preventing alcohol drinking relapse. 1.Brown et al.(1979) Psychopharmacology 64:271-276. 2. Smith et al. (1984) Alcohol 1:193-195. 3. Melis M et al (2007)Eur J Neurosci. 26:2824-2833. 4.Cacace S et al., AlcoholClinExpRes 2012; 36(7):1278-87 5. Thanos et al. J Neurochem.2001;78:1094-1103.

Indicaxanthin (IX) from Opuntia Ficus Indica (OFI) has been shown to exert numerous biological effects both in vitro and in vivo, such as antioxidant, anti-inflammatory, neuro-modulatory activity in rodent models. Our goal was to investigate the eventual neuro-active role of orally assumed fruits containing high levels of IX at nutritionally-relevant amounts in healthy subjects, exploring cortical excitability and plasticity in the human motor cortex (M1). To this purpose, we applied paired-pulse transcranial magnetic stimulation and anodal transcranial direct current stimulation (a-tDCS) in basal conditions and followed the consumption of yellow cactus pear fruits containing IX or white cactus pear fruits devoid of IX (placebo). Furthermore, resting state-functional MRI (rs-fMRI) preliminary acquisitions were performed before and after consumption of the same number of yellow fruits. Our data revealed that the consumption of IX-containing fruits could specifically activate intracortical excitatory circuits, differently from the placebo-controlled group. Furthermore, we found that following the ingestion of IX-containing fruits, elevated network activity of glutamatergic intracortical circuits can homeostatically be restored to baseline levels following a-tDCS stimulation. No significant differences were observed through rs-fMRI acquisitions. These outcomes suggest that IX from OFI increases intracortical excitability of M1 and leads to homeostatic cortical plasticity responses.

Tomato fruits defined as “golden” refer to a food product harvested at an incomplete ripening stage with respect to red tomatoes at full maturation. The aim of this study is to explore the putative influence of “golden tomato” (GT) on Metabolic Syndrome (MetS), especially focusing on the effects on redox homeostasis. Firstly, the differential chemical properties of the GT food matrix were characterized in terms of phytonutrient composition and antioxidant capacities with respect to red tomato (RT). Later, we assessed the biochemical, nutraceutical and eventually disease-modifying potential of GT in vivo in the high-fat-diet rat model of MetS. Our data revealed that GT oral supplementation is able to counterbalance MetS-induced biometric and metabolic modifications. Noteworthy is that this nutritional supplementation proved to reduce plasma oxidant status and improve the endogenous antioxidant barriers, assessed by strong systemic biomarkers. Furthermore, consistently with the reduction of hepatic reactive oxygen and nitrogen species (RONS) levels, treatment with GT markedly reduced the HFD-induced increase in hepatic lipid peroxidation and hepatic steatosis. This research elucidates the importance of food supplementation with GT in the prevention and management of MetS.

Despite a huge effort of the scientific community, the functioning of Long-Term Memory (LTM) processes is still debated and far from being elucidated. Functional and neurophysiological data point to an involvement of Dorsolateral Prefrontal Cortex (DLPFC) in both encoding and retrieval phases. However, the recently proposed Explicit/Implicit Memory Encoding and Retrieval (EIMER) model proposes that LTM at the encoding phase consists of anatomically and chronologically different sub-phases. On this basis, we aimed to investigate the role of right DLPFC during a late-encoding phase by means of low-frequency rTMS. Thirty right-handed healthy subjects were divided into three experimental groups. Inhibitory rTMS was applied over right-DLPFC immediately after the encoding phase (Late-Encoding Group) or before recognition phase (Pre-Recognition Group), 24 h after, of an LTM task. Both groups also received sham stimulation during the non-target phase, while the third group (Sham Group) received only sham stimulation in both phases. The Late-Encoding Group collected a lower number of correct responses compared with Sham Group (p = 0.00), while Pre-Retrieval Group increased accuracy as compared to the Sham Group (p = 0.0). rTMS-inhibition of the right DLPFC seems able to interfere with LTM memory performances when delivered at a late stage of the encoding phase, with opposite effects at the pre-retrieval phase.

Brain activity and behavior are constantly changing (Puig et al., 2014; Disney, 2021). Recent studies in both animal models and humans have revealed that such variations are not random in nature but controlled through slow-acting neuromodulatory systems..., This work was supported by a DFG grant ZA990/1 to DZ. This work was supported by the MSCA EU proposal 841301 - DREAM, European Commission; Horizon 2020 - Research and Innovation Framework Programme to JFRV.

Guanosine (GUO), widely considered a key signaling mediator, is implicated in the regulation of several cellular processes. While its interaction with neural membranes has been described, GUO still is an orphan neuromodulator. It has been postulated that GUO may eventually interact with potassium channels and adenosine (ADO) receptors (ARs), both particularly important for the control of cellular excitability. Accordingly, here, we investigated the effects of GUO on the bioelectric activity of human neuroblastoma SH-SY5Y cells by whole-cell patch-clamp recordings. We first explored the contribution of voltage-dependent K+ channels and, besides this, the role of ARs in the regulation of GUO-dependent cellular electrophysiology. Our data support that GUO is able to specifically modulate K+-dependent outward currents over cell membranes. Importantly, administering ADO along with GUO potentiates its effects. Overall, these results suggested that K+ outward membrane channels may be targeted by GUO with an implication of ADO receptors in SH-SY5Y cells, but also support the hypothesis of a functional interaction of the two ligands. The present research runs through the leitmotif of the deorphanization of GUO, adding insight on the interplay with adenosinergic signaling and suggesting GUO as a powerful modulator of SH-SY5Y excitability.

Metabolic Syndrome (MetS) is an extremely complex disease. A non-balanced diet such as high-fat diet (HFD) induces metabolic dysfunction that could modify redox homeostasis. We here aimed at exploring redox homeostasis in male Wistar rats, following 8 weeks of HFD, correlating the eventual modification of selected biomarkers that could be associated with the clinical manifestations of MetS. Therefore, we selected parameters relative to both the glucose tolerance and lipid altered metabolism, but also oxidative pattern. We assessed some biomarkers of oxidative stress i.e., thiols balance, lipid peroxidation and antioxidant barriers, via the use of specific biochemical assays, individuating eventual cross correlation with parameters relative to MetS through a Principal Component Analysis (PCA). The present study shows that 8 weeks of HFD induce MetS in rats, altering glucose and lipid homeostasis and increasing visceral adipose tissue, but also impairing the physiological antioxidant responses that could not counteract the oxidative stress condition. Crucially, cross-correlation analysis suggested that the assessment of specific oxidative stress parameters reported here can provide information comparable to the more widely acquired biomarkers of Mets such as glucose tolerance. Lastly, hepatic steatosis in association with the oxidative stress condition was also highlighted by histological analysis. This research will elucidate the fundamental impact of these oxidative stress parameters on MetS induced in the HFD rat model, tracing paths for developing prevention approaches.

The process of aging commonly features a gradual deterioration in cognitive performance and, in particular, the decline of memory. Despite the increased longevity of the world's population, the prevalence of neurodegenerative conditions, such as dementia, continues to be a major burden on public health, and consequently, the latest research has been focused on memory and aging. Currently, the failure of episodic and Prospective memory (PM) is one of the main complaints in the elderly, considered among the early symptoms of dementia. It is therefore increasingly important to define more clearly the boundaries between normal and pathological aging. Recently, researchers have begun to build and apply Virtual Environments (VE) to the explicit purpose of better understanding the performance of episodic and PM in complex and realistic contexts, with the perspective of further developing effective training procedures that depend on reliable cognitive assessment methods. Virtual technology offers higher levels of realism than "pen and paper" testing and at the same time more experimental control than naturalistic settings. In this mini-review article, we examine the outcomes of recently available studies on virtual reality technology applications developed for the assessment and improvement of episodic and/or PM. To consider the latest technology, we selected 29 articles that have been published in the last 10 years. These documents show that VR-based technologies can provide a valid basis for screening and treatment and, through increased sensory stimulation and enriched environments reproducing the scenarios of everyday life, could represent effective stimulating experiences even in pathological aging.

Cannabinoids (CB), transient receptors potential vanilloid type 1 (TRPV1) and nitric oxide (NO) were found to be interlinked in regulating some neuronal functions such as membrane excitability and synaptic transmission. TRPV1 play a fundamental role since it represents a synaptic target for CB that triggers several downstream cellular pathways. In this regard, recent evidence report that TRPV1 could influence NO production by modulating neuronal NO synthase (nNOS) activity. In the present research, we pointed to manipulate nNOS function to assess its role on TRPV1 signalling in hyperexcitability conditions elicited in the dentate gyrus of hippocampal formation. The activation of TRPV1 receptors is achieved by administering capsaicin (CAP), the main TRPV1 agonist exerting a widely reported proepileptic effects. In order to focus on nNOS activity, we used 7-nitroindazole (7NI), nNOS inhibitor, or L-Arginine (ARG), NO precursor, before CAP. Then, the effects of each of these co-administration protocols were tested in presence of WIN 55,212, a CB agonist. The study was conducted in rats using an electrically-induced acute model of temporal lobe hyperexcitability, the Maximal Dentate Activation (MDA), considering different indicators of paroxysmal activity such as: percentage of responses to electrical stimulation, MDA discharge parameters and threshold current intensity for MDA. Data showed that the excitatory effects of CAP were reduced by 7NI and enhanced by ARG pretreatments, respectively. In addition, the co-treatment with WIN counteracted CAP effect, substantially resulting in an inhibitory effect. Finally, the CAP-WIN functional interaction appeared to be modulated by interfering with NO signalling since 7NI increased the inhibitory effect induced by the co-treatment with CAP and WIN, whereas ARG reduced it. These findings suggest that nNOS function could be involved in the CB/TRPV1 signalling and shed light on a new putative cannabinoid-related control of neuronal hyperexcitability in the hippocampus.

Several studies have recently investigated the role of nutraceuticals in complex pathophysiological processes such as oxidative damages, inflammatory conditions and excitotoxicity. In this regard, the effects of nutraceuticals on basic functions of neuronal cells, such as excitability, are still poorly investigated. For this reason, the possible modulation of neuronal excitability by phytochemicals (PhC) could represent an interesting field of research given that excitotoxicity phenomena are involved in neurodegenerative alterations leading, for example, to Alzheimer's disease. The present study was focused on indicaxanthin from Opuntia ficus indica, a bioactive betalain pigment, with a proven antioxidant and anti-inflammatory potential, previously found to cross blood-brain barrier (BBB) and to modulate the bioelectric activity of hippocampal neurons. On this basis, we aimed at detecting the specific brain areas where indicaxanthin localizes after oral administration at dietary-achievable amounts and highlighting eventual local effects on the excitability of single neuronal units. HPLC analysis of brain tissue 1 h after ingestion of 2 mu mol/kg indicaxanthin indicated that the phytochemical accumulates in cortex, hippocampus, diencephalon, brainstem and cerebellum, but not in the striato-pallidal complex. Then, electrophysiological recordings, applying the microiontophoretic technique, were carried out with different amounts of indicaxanthin (0.34, 0.17, 0.085 ng/neuron) to assess whether indicaxanthin influenced the neuronal firing rate. The data showed that the bioelectric activity of neurons belonging to different brain areas was modulated after local injection of indicaxanthin, mainly with dose-related responses. A predominating inhibitory effect was observed, suggesting a possible novel beneficial effect of indicaxanthin in reducing cell excitability. These findings can constitute a new rationale for exploring biological mechanisms through which PhC could modulate neuronal function with a relapse on complex cognitive brain process and related neurodegenerative conditions.