A Brainstem reticulotegmental neural ensemble drives acoustic startle reflexes
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ABSTRACT:
SUBMITTER: Guo W
PROVIDER: S-EPMC8568936 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the developing brain, groups of neurons organize into functional circuits that direct diverse behaviors. One such behavior is the evolutionarily conserved acoustic startle response, which in zebrafish is mediated by a well-defined hindbrain circuit. While numerous molecular pathways that guide neurons to their synaptic partners have been identified, it is unclear if and to what extent distinct neuron populations in the startle circuit utilize shared molecular pathways to ensure coordinated development. Here, we show that the planar cell polarity (PCP)-associated atypical cadherins Celsr3 and Celsr2, as well as the Celsr binding partner Frizzled 3a/Fzd3a, are critical for axon guidance of two neuron types that form synapses with each other: the command-like neuron Mauthner cells that drive the acoustic startle escape response, and spiral fiber neurons which provide excitatory input to Mauthner cells. We find that Mauthner axon growth towards synaptic targets is vital for Mauthner survival. We also demonstrate that symmetric spiral fiber input to Mauthner cells is critical for escape direction, which is necessary to respond to directional threats. Moreover, we identify distinct roles for Celsr3 and Celsr2, as Celsr3 is required for startle circuit development while Celsr2 is dispensable, though Celsr2 can partially compensate for loss of Celsr3 in Mauthner cells. This contrasts with facial branchiomotor neuron migration in the hindbrain, which requires Celsr2 while we find that Celsr3 is dispensable. Combined, our data uncover critical and distinct roles for individual PCP components during assembly of the acoustic startle hindbrain circuit.
| S-EPMC10942420 | biostudies-literature
Project description: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. Here, we investigated the anatomical origin and functional role of these inputs using a multidisciplinary approach that combines morphological, electrophysiological and behavioral techniques. Anterograde tracer injections into the cochlea suggest that CRNs somata and dendrites receive inputs depending, respectively, on their basal or apical cochlear origin. Confocal colocalization experiments demonstrated that these cochlear inputs are immunopositive for the vesicular glutamate transporter 1 (VGLUT1). Using extracellular recordings in vivo followed by subsequent tracer injections, we investigated the response of PnC neurons after contra-, ipsi-, and bilateral acoustic stimulation and identified the source of their auditory afferents. Our results showed that the binaural firing rate of PnC neurons was higher than the monaural, exhibiting higher spike discharges with contralateral than ipsilateral acoustic stimulations. Our histological analysis confirmed the CRNs as the principal source of short-latency acoustic inputs, and indicated that other areas of the cochlear nucleus complex are not likely to innervate PnC. Behaviorally, we observed a strong reduction of ASR amplitude in monaural earplugged rats that corresponds with the binaural summation process shown in our electrophysiological findings. Our study contributes to understand better the role of neuronal mechanisms in auditory alerting behaviors and provides strong evidence that the CRNs-PnC pathway mediates fast neurotransmission and binaural summation of the ASR.
| S-EPMC4110630 | biostudies-literature
Project description:The prevalence of Toxoplasma gondii (TOXO) infection in schizophrenia (SCZ) is elevated compared to controls (odds ratio=2.73). TOXO infection is associated with psychomotor slowing in rodents and non-psychiatric humans. Latency of the acoustic startle response, an index of neural processing speed, is the time it takes for a startling stimulus to elicit the reflexive response through a three-synapse subcortical circuit. We report a significant slowing of latency in TOXO seropositive SCZ vs. seronegative SCZ, and in TOXO seropositive controls vs. seronegative controls. Latency was likewise slower in SCZ subjects than in controls. These findings indicate a slowing of neural processing speed with chronic TOXO infection; the slowest startle latency was seen in the TOXO seropositive SCZ group.
| S-EPMC3786776 | biostudies-literature
Project description:Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68-90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single-nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate?<?0.05). Pathway analysis of these genes revealed enrichment for relevant biological processes including neural transmission (p?=?0.0029), synaptic transmission (p?=?0.0032), and neuronal development (p?=?0.024). The subsequent SNP-based replication analysis revealed a strong association of onset latency with the SNP rs901561 on the neuregulin gene (NRG1) in an additive model (beta?=?0.21, p?=?0.001), indicating that subjects with the AA and AG genotypes had slower mean latency than subjects with GG genotype. In conclusion, startle latency, a highly heritable measure that is slowed in schizophrenia, may be a useful biological probe for genetic contributions to psychotic disorders. Our analyses in two independent populations point to a significant prediction of startle latency by genetic variation in NRG1.
| S-EPMC5498475 | biostudies-literature
Project description:Functional role of the acoustic reflex in preventing over stimulation of the inner auditory system by decreasing sound intensity along with the previous reports of acoustic reflex abnormalities in individuals having hyperacusis point towards the involvement of acoustic reflex deficit in the origin of hyperacusis especially when any medical condition leading to hyperacusis is not associated. However this issue remains contradictory owing to limited comprehensive investigation. This study was undertaken to ascertain the relationship between hyperacusis and the acoustic reflex. Threshold, amplitude and latency of the acoustic reflex were measured in two different groups of individuals having hyperacusis; Group 1: 14 individuals having hyperacusis with hearing loss (HwHL) and Group 2: 17 individuals having hyperacusis without hearing loss (HwoHL). Control group (Group 3) consisted of 15 normal hearing individuals who never experienced hyperacusis. Result showed a significant group effect on all the measured characteristics of the acoustic reflex. ARTs were found to be significantly higher in HwHL and HwoHL when compared to NHwoH. ARTs were statistically similar for HwoHL and NHwoH. HwoHL's ARAs and ARLs were significantly smaller and prolonged, respectively, when compared to HwHL and NHwoH. HwHL and NHwoH had statistically similar ARAs and ARLs. This study confirms acoustic reflex abnormalities in some individuals having hyperacusis with or without hearing loss. It further highlight the importance of involving acoustic reflex testing in the assessment of hyperacusis especially when hyperacusis is not associated with hearing loss or any other medical condition that may lead to hyperacusis.
| S-EPMC7544758 | biostudies-literature
Project description:Prepulse inhibition (PPI) is an acoustic startle paradigm that has been used as an operational measure of sensorimotor gating. Many patients with schizophrenia have impaired PPI, and several lines of evidence suggest that PPI may represent a heritable endophenotype in this disease. We examined startle magnitude and latencies in 40 schizophrenia patients, 58 first-degree relatives of these patients, and 100 healthy controls. After removing low-startlers, we investigated PPI and startle habituation in 34 schizophrenia patients, 43 relatives, and 86 control subjects. Heritability analyses were conducted using a variance-component approach. We found significant heritability of 45% for PPI at the 60-ms interval and 67% for startle magnitude. Onset latency heritability estimates ranged between 39% and 90% across trial types, and those for peak latency ranged from 29% to 68%. Heritability of startle habituation trended toward significance at 31%. We did not detect differences between controls and either schizophrenia patients or their family members for PPI, startle magnitude, or habituation. Startle latencies were generally longer in schizophrenia patients than controls. The heritability findings give impetus to applying genetic analyses to PPI variables, and suggest that startle latency may also be a useful measure in the study of potential endophenotypes for schizophrenia.
| S-EPMC2902662 | biostudies-literature
Project description:Objectivesto characterize differences in wideband power reflectance for ears with and without cochlear implants (CIs), to describe electrically evoked stapedial reflex (eSR)-induced changes in reflectance, and to evaluate the benefit of a broadband probe for reflex threshold determination for CI recipients. It was hypothesized that reflectance patterns in ears with CIs would be consistent with increased middle ear stiffness and that reflex thresholds measured with a broadband probe would be lower compared with thresholds obtained with a single-frequency probe.DesignEleven CI recipients participated in both wideband reflectance and eSR testing. Ipsilateral reflexes were measured with three probes: a broadband chirp (swept from 200 to 8000 Hz), a 226 Hz tone, and a 678 Hz tone. Wideband reflectance measures acquired from 28 adults without CIs and with normal middle ear function served as a normative data set for comparison.ResultsConsidering the group data, average reflectance was significantly greater for ears with CIs across 250 to 891 Hz and 4238 to 4490 Hz compared with the normative data set, although individual reflectance curves were variable. Some CI recipients also had low 226 Hz admittance, which contributed to the group finding, considering the control group had clinically normal 226 Hz admittance by design. Electrically evoked stapedial reflexes were measurable in nine of 14 ears (64.3%) and in 24 of 46 electrodes (52.5%) tested. Reflex-induced changes in reflectance patterns were unique to the participant/ear, but similar across activators (electrodes) within a given ear. In addition, reflectance values at or above 1000 Hz were affected most by activating the stapedial reflex, even in ears with clinically normal 226 Hz admittance. This is a higher-frequency range than has been reported for acoustically evoked reflex-induced reflectance changes and is consistent with increased middle ear stiffness at rest. Electrically evoked reflexes could be measured more often with the 678 Hz or the broadband probe compared with the 226 Hz probe tone. Although reflex thresholds were lower with the broadband probe compared with the 678 Hz probe in 16 of 24 conditions, this was not a statistically significant finding (Wilcoxon signed-rank test; p = 0.072).ConclusionsThe applications of wideband acoustic immittance measurements (reflectance and reflexes) should also be considered for ears with CIs. Further work is needed to describe changes across time in ears with CIs to more fully understand the reflectance pattern indicating increased middle ear stiffness and to optimize measuring eSRs with a broadband probe.
| S-EPMC8039839 | biostudies-literature
Project description:Filtering mechanisms prevent a continuous stream of sensory information from swamping perception, leading to diminished focal attention and cognitive processing. Mechanisms for sensory gating are commonly studied using prepulse inhibition, a paradigm that measures the regulated transmission of auditory information to the startle circuit; however, the underlying neuronal pathways are unresolved. Using large-scale calcium imaging, optogenetics, and laser ablations, we reveal a cluster of 30 morphologically identified neurons in zebrafish that suppress the transmission of auditory signals during prepulse inhibition. These neurons project to a key sensorimotor interface in the startle circuit-the termination zone of auditory afferents on the dendrite of a startle command neuron. Direct measurement of auditory nerve neurotransmitter release revealed selective presynaptic inhibition of sensory transmission to the startle circuit, sparing signaling to other brain regions. Our results provide the first cellular resolution circuit for prepulse inhibition in a vertebrate, revealing a central role for presynaptic gating of sensory information to a brainstem motor circuit.
| S-EPMC6410737 | biostudies-literature
Project description:The objective of this protocol is to provide a detailed description for the construction and use of a behavioral apparatus, the zBox, for high-throughput behavioral measurements in larval zebrafish (Danio rerio). The zBox is used to measure behavior in multiple individuals simultaneously. Individual fish are housed in wells of multi-well plates and receive acoustic/vibration stimuli with simultaneous recording of behavior. Automated analysis of behavioral movies is performed with MATLAB scripts. This protocol was adapted from two of our previously published papers (Levitz et al., 2013; Pantoja et al., 2016). The zBox provides an easy to setup flexible platform for behavioral experiments in zebrafish larvae.
| S-EPMC5526351 | biostudies-literature
Project description:Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia.
| S-EPMC5534953 | biostudies-literature