Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.

This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6).

The role of the Ventral Nucleus of the Trapezoid Body in the auditory prepulse inhibition of the acoustic startle reflex.

Cholinergic signaling is essential to mediate the auditory prepulse inhibition (PPI), an operational measure of sensorimotor gating, that refers to the reduction of the acoustic startle reflex (ASR) when a low-intensity, non-startling acoustic stimulus (the prepulse) is presented just before the onset of the acoustic startle stimulus. The cochlear root neurons (CRNs) are the first cells of the ASR circuit to receive cholinergic inputs from non-olivocochlear neurons of the ventral nucleus of the trapezoid body (VNTB) and subsequently decrease their neuronal activity in response to auditory prepulses. Yet, the contribution of the VNTB-CRNs pathway to the mediation of PPI has not been fully elucidated.

Delving into the significance of the His289Tyr single-nucleotide polymorphism in the glutamate ionotropic receptor kainate-1 () gene of a genetically audiogenic seizure model.

Genetic abnormalities affecting glutamate receptors are central to excitatory overload-driven neuronal mechanisms that culminate in seizures, making them pivotal targets in epilepsy research. Increasingly used to advance this field, the genetically audiogenic seizure hamster from Salamanca (GASH/Sal) exhibits generalized seizures triggered by high-intensity acoustic stimulation and harbors significant genetic variants recently identified through whole-exome sequencing. Here, we addressed the influence of the missense single-nucleotide polymorphism (C9586732T, p.

Enhanced Membrane Incorporation of H289Y Mutant GluK1 Receptors from the Audiogenic Seizure-Prone GASH/Sal Model: Functional and Morphological Impacts on Oocytes.

Epilepsy is a neurological disorder characterized by abnormal neuronal excitability, with glutamate playing a key role as the predominant excitatory neurotransmitter involved in seizures. Animal models of epilepsy are crucial in advancing epilepsy research by faithfully replicating the diverse symptoms of this disorder. In particular, the GASH/Sal (genetically audiogenic seizure-prone hamster from Salamanca) model exhibits seizures resembling human generalized tonic-clonic convulsions.

The nuclei of the lateral lemniscus: unexpected players in the descending auditory pathway.

Introduction: In the mammalian auditory pathway, the nuclei of the lateral lemniscus (NLL) are thought to be exclusively involved in the bottom-up transmission of auditory information. However, our repeated observation of numerous NLL neurons labeled after injection of retrograde tracers into the superior olivary complex (SOC) led us to systematically investigate with retrograde tracers the descending projections from the NLL to the SOC of the rat.

Methods: We performed large injections of FluoroGold into the SOC to determine NLL contributions to descending projections, and focal injections of biotinylated dextran amine (BDA) to pinpoint the specific nuclei of the SOC innervated by each NLL.

Proteomic and Bioinformatic Tools to Identify Potential Hub Proteins in the Audiogenic Seizure-Prone Hamster GASH/Sal.

The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca) is a model of audiogenic seizures with the epileptogenic focus localized in the inferior colliculus (IC). The sound-induced seizures exhibit a short latency (7-9 s), which implies innate protein disturbances in the IC as a basis for seizure susceptibility and generation. Here, we aim to study the protein profile in the GASH/Sal IC in comparison to controls.

Distribution of the Cannabinoid Receptor Type 1 in the Brain of the Genetically Audiogenic Seizure-Prone Hamster GASH/Sal.

The endocannabinoid system modulates epileptic seizures by regulating neuronal excitability. It has become clear that agonist activation of central type I cannabinoid receptors (CB1R) reduces epileptogenesis in pre-clinical animal models of epilepsy. The audiogenic seizure-prone hamster GASH/Sal is a reliable experimental model of generalized tonic-clonic seizures in response to intense sound stimulation.

Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures.

Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic-clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs.

Prepulse Inhibition of the Auditory Startle Reflex Assessment as a Hallmark of Brainstem Sensorimotor Gating Mechanisms.

When a low-salience stimulus of any type of sensory modality-auditory, visual, tactile-immediately precedes an unexpected startle-like stimulus, such as the acoustic startle reflex, the startle motor reaction becomes less pronounced or is even abolished. This phenomenon is known as prepulse inhibition (PPI), and it provides a quantitative measure of central processing by filtering out irrelevant stimuli. As PPI implies plasticity of a reflex and is related to automatic or attentional processes, depending on the interstimulus intervals, this behavioral paradigm might be considered a potential marker of short- and long-term plasticity.

Inferior Colliculus Transcriptome After Status Epilepticus in the Genetically Audiogenic Seizure-Prone Hamster GASH/Sal.

The Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal), an animal model of reflex epilepsy, exhibits generalized tonic-clonic seizures in response to loud sound with the epileptogenic focus localized in the inferior colliculus (IC). Ictal events in seizure-prone strains cause gene deregulation in the epileptogenic focus, which can provide insights into the epileptogenic mechanisms. Thus, the present study aimed to determine the expression profile of key genes in the IC of the GASH/Sal after the status epilepticus.

Morphological and molecular correlates of altered hearing sensitivity in the genetically audiogenic seizure-prone hamster GASH/Sal.

Rodent models of audiogenic seizures, in which seizures are precipitated by an abnormal response of the brain to auditory stimuli, are crucial to investigate the neural bases underlying ictogenesis. Despite significant advances in understanding seizure generation in the inferior colliculus, namely the epileptogenic nucleus, little is known about the contribution of lower auditory stations to the seizure-prone network. Here, we examined the cochlea and cochlear nucleus of the genetic audiogenic seizure hamster from Salamanca (GASH/Sal), a model of reflex epilepsy that exhibits generalized tonic-clonic seizures in response to loud sound.

Analysis of gene variants in the GASH/Sal model of epilepsy.

Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients.

Top Common Differentially Expressed Genes in the Epileptogenic Nucleus of Two Strains of Rodents Susceptible to Audiogenic Seizures: WAR and GASH/Sal.

The Wistar Audiogenic Rat (WAR) and the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) strains are audiogenic epilepsy models, in which seizures are triggered by acoustic stimulation. These strains were developed by selective reproduction and have a genetic background with minimal or no variation. In the current study, we evaluated the transcriptome of the inferior colliculus, the epileptogenic nucleus, of both audiogenic models, in order to get insights into common molecular aspects associated to their epileptic phenotype.

Molecular tools for the characterization of seizure susceptibility in genetic rodent models of epilepsy.

Epilepsy is a chronic neurological disorder characterized by abnormal neuronal activity that arises from imbalances between excitatory and inhibitory synapses, which are highly correlated to functional and structural changes in specific brain regions. The difference between the normal and the epileptic brain may harbor genetic alterations, gene expression changes, and/or protein alterations in the epileptogenic nucleus. It is becoming increasingly clear that such differences contribute to the development of distinct epilepsy phenotypes.

Relations between Sensorimotor Integration and Speech Disorders in Parkinson's Disease.

Background: Sensorimotor integration mechanisms can be affected by many factors, among which are those involving neuromuscular disorders. Parkinson's disease (PD) is characterized by well-known motor symptoms, among which lately have been included motor speech deficits. Measurement of the acoustic startle reflex (ASR) and its modulations (prepulse inhibition and prepulse facilitation, PPI and PPF respectively) represent a simple and quantifiable tool to assess sensorimotor function.

Morphological correlates of sex differences in acoustic startle response and prepulse inhibition through projections from locus coeruleus to cochlear root neurons.

The noradrenergic locus coeruleus (LC) plays an important role in the promotion and maintenance of arousal and alertness. Our group recently described coerulean projections to cochlear root neurons (CRNs), the first relay of the primary acoustic startle reflex (ASR) circuit. However, the role of the LC in the ASR and its modulation, prepulse inhibition (PPI), is not clear.

Morphofunctional alterations in the olivocochlear efferent system of the genetic audiogenic seizure-prone hamster GASH:Sal.

The genetic audiogenic seizure hamster (GASH:Sal) is a model of a form of reflex epilepsy that is manifested as generalized tonic-clonic seizures induced by external acoustic stimulation. The morphofunctional alterations in the auditory system of the GASH:Sal that may contribute to seizure susceptibility have not been thoroughly determined. In this study, we analyzed the olivocochlear efferent system of the GASH:Sal from the organ of Corti, including outer and inner hair cells, to the olivocochlear neurons, including shell, lateral, and medial olivocochlear (LOC and MOC) neurons that innervate the cochlear receptor.

Overexpression of the immediate-early genes Egr1, Egr2, and Egr3 in two strains of rodents susceptible to audiogenic seizures.

Genetic animal models of epilepsy are an important tool for further understanding the basic cellular mechanisms underlying epileptogenesis and for developing novel antiepileptic drugs. We conducted a comparative study of gene expression in the inferior colliculus, a nucleus that triggers audiogenic seizures, using two animal models, the Wistar audiogenic rat (WAR) and the genetic audiogenic seizure hamster (GASH:Sal). For this purpose, both models were exposed to high intensity auditory stimulation, and 60min later, the inferior colliculi were collected.

Origin and function of short-latency inputs to the neural substrates underlying the acoustic startle reflex.

The acoustic startle reflex (ASR) is a survival mechanism of alarm, which rapidly alerts the organism to a sudden loud auditory stimulus. In rats, the primary ASR circuit encompasses three serially connected structures: cochlear root neurons (CRNs), neurons in the caudal pontine reticular nucleus (PnC), and motoneurons in the medulla and spinal cord. It is well-established that both CRNs and PnC neurons receive short-latency auditory inputs to mediate the ASR.

The noradrenergic projection from the locus coeruleus to the cochlear root neurons in rats.

The cochlear root neurons (CRNs) are key components of the primary acoustic startle circuit; mediating auditory alert and escape behaviors in rats. They receive a great variety of inputs which serve to elicit and modulate the acoustic startle reflex (ASR). Recently, our group has suggested that CRNs receive inputs from the locus coeruleus (LC), a noradrenergic nucleus which participates in attention and alertness.

A fast cholinergic modulation of the primary acoustic startle circuit in rats.

Cochlear root neurons (CRNs) are the first brainstem neurons which initiate and participate in the full expression of the acoustic startle reflex. Although it has been suggested that a cholinergic pathway from the ventral nucleus of the trapezoid body (VNTB) conveys auditory prepulses to the CRNs, the neuronal origin of the VNTB-CRNs projection and the role it may play in the cochlear root nucleus remain uncertain. To determine the VNTB neuronal type which projects to CRNs, we performed tract-tracing experiments combined with mechanical lesions, and morphometric analyses.

Chronic administration of risperidone in a rat model of schizophrenia: a behavioural, morphological and molecular study.

In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D(2) and 5-HT(2A) receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV.

The selective neurotoxin DSP-4 impairs the noradrenergic projections from the locus coeruleus to the inferior colliculus in rats.

The inferior colliculus (IC) and the locus coeruleus (LC) are two midbrain nuclei that integrate multimodal information and play a major role in novelty detection to elicit an orienting response. Despite the reciprocal connections between these two structures, the projection pattern and target areas of the LC within the subdivisions of the rat IC are still unknown. Here, we used tract-tracing approaches combined with immunohistochemistry, densitometry, and confocal microscopy (CM) analysis to describe a projection from the LC to the IC.