Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats
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ABSTRACT:
SUBMITTER: Tamaoki Y
PROVIDER: S-EPMC10759431 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports critical aspects of auditory behavior but has not been extensively characterized. Previous studies demonstrated that activity in IC is altered by focal electrical stimulation and pharmacological inactivation of AC, but these methods lack the ability to selectively manipulate projection neurons. We measured the effects of selective optogenetic modulation of cortico-collicular feedback projections on IC sound responses in mice. Activation of feedback increased spontaneous activity and decreased stimulus selectivity in IC, whereas suppression had no effect. To further understand how microcircuits in AC may control collicular activity, we optogenetically modulated the activity of different cortical neuronal subtypes, specifically parvalbumin-positive (PV) and somatostatin-positive (SST) inhibitory interneurons. We found that modulating the activity of either type of interneuron did not affect IC sound-evoked activity. Combined, our results identify that activation of excitatory projections, but not inhibition-driven changes in cortical activity, affects collicular sound responses.
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Project description:Autism spectrum disorder (ASD) is characterized by impaired socio-communicational function, repetitive and restricted behaviors. Valproic acid (VPA) was reported to increase the prevalence of ASD in humans as a consequence of its use during pregnancy. VPA treatment also induces autistic-like behaviors in the offspring of rats after prenatal exposure; hence it is a preclinical disease model with high translational value. In the present study, our aim was to characterize ASD relevant behaviors of socially housed, individually identified male rats in automated home cages. The natural behavior of rats was assessed by monitoring their visits to drinking bottles in an environment without human influence aiming at reducing interventional stress. Although rodents normally tend to explore their new environment, prenatally VPA-treated rats showed a drastic impairment in initial and long-term exploratory behavior throughout their stay in the automated cage. Furthermore, VPA rats displayed psychogenic polydipsia (PPD) as well as altered circadian activity. In the competitive situation of strict water deprivation controls switched to an uneven resource sharing and only a few dominant animals had access to water. In VPA animals similar hierarchy-related changes were completely absent. While the control rats secured their chance to drink with frequent reentering visits, thereby "guarding" the water resource, VPA animals did not switch to uneven sharing and displayed no evidence of guarding behavior.
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Project description:BackgroundEpidemiological evidence indicates epilepsy is more common in patients with autism spectrum disorders (ASD) (20-25%) than in the general population. The aim of this project was to analyze seizure susceptibility in developing rats prenatally exposed to valproic acid (VPA) as autism model.MethodsPregnant females were injected with VPA during the twelfth embryonic day. Seizures were induced in fourteen-days-old rat pups using two models of convulsions: pentylenetetrazole (PTZ) and lithium-pilocarpine (Li-Pilo).ResultsTwo subgroups with different PTZ-induced seizure susceptibility in rats exposed to VPA were found: a high susceptibility (VPA+) (28/42, seizure severity 5) and a low susceptibility (VPA-) (14/42, seizure severity 2). The VPA+ subgroup exhibited an increased duration of the generalized tonic-clonic seizure (GTCS; 45 ± 2.7 min), a higher number of rats showed several GTCS (14/28) and developed status epilepticus (SE) after PTZ injection (19/27) compared with control animals (36.6 ± 1.9 min; 10/39; 15/39, respectively). No differences in seizure severity, latency or duration of SE induced by Li-Pilo were detected between VPA and control animals.DiscussionPrenatal VPA modifies the susceptibility to PTZ-induced seizures in developing rats, which may be linked to an alteration in the GABAergic transmission. These findings contribute to a better understanding of the comorbidity between autism and epilepsy.
| S-EPMC5131616 | biostudies-literature
Project description:Individuals with SHANK3 mutations have severely impaired receptive and expressive language abilities. While brain responses are known to be abnormal in these individuals, the auditory cortex response to sound has remained largely understudied. In this study, we document the auditory cortex response to speech and non-speech sounds in the novel Shank3-deficient rat model. We predicted that the auditory cortex response to sounds would be impaired in Shank3-deficient rats. We found that auditory cortex responses were weaker in Shank3 heterozygous rats compared to wild-type rats. Additionally, Shank3 heterozygous responses had less spontaneous auditory cortex firing and were unable to respond well to rapid trains of noise bursts. The rat model of the auditory impairments in SHANK3 mutation could be used to test potential rehabilitation or drug therapies to improve the communication impairments observed in individuals with Phelan-McDermid syndrome. Autism Res 2018, 11: 59-68. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY:Individuals with SHANK3 mutations have severely impaired language abilities, yet the auditory cortex response to sound has remained largely understudied. In this study, we found that auditory cortex responses were weaker and were unable to respond well to rapid sounds in Shank3-deficient rats compared to control rats. The rat model of the auditory impairments in SHANK3 mutation could be used to test potential rehabilitation or drug therapies to improve the communication impairments observed in individuals with Phelan-McDermid syndrome.
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Project description:The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of Autism Spectrum Disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. However, surprisingly little is known about the cellular, molecular, or genetic changes that occur in the amygdala over development in ASD individuals or rodent models. We examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD.
2017-07-03 | GSE98777 | GEO
Project description:BackgroundThe amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD.MethodsRat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development.ResultsEffects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed.ConclusionsAs behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes.
| S-EPMC5539636 | biostudies-literature
Project description:The inferior colliculus (IC) is a critical centre for the binaural processing of auditory information. However, previous studies have mainly focused on the central nucleus of the inferior colliculus (ICC), and less is known about the dorsal nucleus of the inferior colliculus (ICD). Here, we first examined the characteristics of the neuronal responses in the mouse ICD and compared them with those in the inferior colliculus under binaural and monaural conditions using in vivo loose-patch recordings. ICD neurons exhibited stronger responses to ipsilateral sound stimulation and better binaural summation than those of ICC neurons, which indicated a role for the ICD in binaural hearing integration. According to the abundant interactions between bilateral ICDs detected using retrograde virus tracing, we further studied the effect of unilateral ICD silencing on the contralateral ICD. After lidocaine was applied, the responses of some ICD neurons (13/26), especially those to ipsilateral auditory stimuli, decreased. Using whole-cell recording and optogenetic methods, we investigated the underlying neuronal circuits and synaptic mechanisms of binaural auditory information processing in the ICD. The unilateral ICD provides both excitatory and inhibitory projections to the opposite ICD, and the advantaged excitatory inputs may be responsible for the enhanced ipsilateral responses and binaural summation of ICD neurons. Based on these results, the contralateral ICD might modulate the ipsilateral responses of the neurons and binaural hearing.
| S-EPMC9061965 | biostudies-literature
Project description:Deep brain stimulation (DBS) of the colliculus inferior (IC) improves haloperidol-induced catalepsy and induces paradoxal kinesia in rats. Since the IC is part of the brain aversive system, DBS of this structure has long been related to aversive behavior in rats limiting its clinical use. This study aimed to improve intracollicular DBS parameters in order to avoid anxiogenic side effects while preserving motor improvements in rats. Catalepsy was induced by systemic haloperidol (0.5mg/kg) and after 60 min the bar test was performed during which a given rat received continuous (5 min, with or without pre-stimulation) or intermittent (5 x 1 min) DBS (30Hz, 200-600μA, pulse width 100μs). Only continuous DBS with pre-stimulation reduced catalepsy time. The rats were also submitted to the elevated plus maze (EPM) test and received either continuous stimulation with or without pre-stimulation, or sham treatment. Only rats receiving continuous DBS with pre-stimulation increased the time spent and the number of entries into the open arms of the EPM suggesting an anxiolytic effect. The present intracollicular DBS parameters induced motor improvements without any evidence of aversive behavior, pointing to the IC as an alternative DBS target to induce paradoxical kinesia improving motor deficits in parkinsonian patients.
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Project description:The cortico-collicular pathway is a bilateral excitatory projection from the cortex to the inferior colliculus (IC). It is asymmetric and predominantly ipsilateral. Using microarrays and RT-qPCR we analyzed changes in gene expression in the IC after unilateral lesions of the auditory cortex, comparing the ICs ipsi- and contralateral to the lesioned side. At 15 days after surgery there were mainly changes in gene expression in the IC ipsilateral to the lesion. Regulation primarily involved inflammatory cascade genes, suggesting a direct effect of degeneration rather than a neuronal plastic reorganization. Ninety days after the cortical lesion the ipsilateral IC showed a significant up-regulation of genes involved in apoptosis and axonal regeneration combined with a down-regulation of genes involved in neurotransmission, synaptic growth, and gap junction assembly. In contrast, the contralateral IC at 90 days post-lesion showed an up-regulation in genes primarily related to neurotransmission, cell proliferation, and synaptic growth. There was also a down-regulation in autophagy and neuroprotection genes. These findings suggest that the reorganization in the IC after descending pathway deafferentation is a long-term process involving extensive changes in gene expression regulation. Regulated genes are involved in many different neuronal functions, and the number and gene rearrangement profile seems to depend on the density of loss of the auditory cortical inputs.
| S-EPMC3516126 | biostudies-literature
Project description:Experiments in animal models indicate that inferior colliculus (IC), the primary auditory midbrain structure, represents sound frequency in a particular spatial organization, a tonotopy, that proceeds from dorsal and superficial to ventral and deeper tissue. Experiments are presented that use high-resolution, sparse-sampling functional magnetic resonance imaging (fMRI) at 3 T to determine if tonotopic gradients can be reliably measured in human IC using high-resolution fMRI. Stimuli were sequences of bandpass-filtered noise with different center frequencies, presented sequentially while fMRI data were collected. Four subjects performed an adaptive frequency-discrimination task throughout the experiment. Results show statistically significant tonotopic gradients within both ICs of all subjects. Frequency gradients as a function of depth were measured using surface-based analysis methods that make virtual penetrations into the IC tissue. This organization was evident over substantial portions of the IC, at locations that are consistent with the expected location of the central nucleus of IC. The results confirm a laminar tonotopy in the human IC at 3 T, but with a heterogeneous, patchy character. The success of these surface-based analysis methods will enable more detailed non-invasive explorations of the functional architecture of other subcortical human auditory structures that have complex, laminar organization.
| S-EPMC3776955 | biostudies-literature