Neural mapping of prepulse-induced startle reflex modulation as indices of sensory information processing in healthy and clinical populations: A systematic review

© 2021 The Authors. Startle reflex is modulated when a weaker sensory stimulus (“prepulse”) precedes a startling stimulus (“pulse”). Prepulse Inhibition (PPI) is the attenuation of the startle reflex (prepulse precedes pulse by 30–500 ms), whereas Prepulse Facilitation (PPF) is the enhancement of the startle reflex (prepulse precedes pulse by 500–6000 ms). Here, we critically appraise human studies using functional neuroimaging to establish brain regions associated with PPI and PPF. Of 10 studies, nine studies revealed thalamic, striatal and frontal lobe activation during PPI in healthy groups, and activation deficits in the cortico-striato-pallido-thalamic circuitry in schizophrenia (three studies) and Tourette Syndrome (two studies). One study revealed a shared network for PPI and PPF in frontal regions and cerebellum, with PPF networks recruiting superior medial gyrus and cingulate cortex. The main gaps in the literature are (i) limited PPF research and whether PPI and PPF operate on separate/shared networks, (ii) no data on sex differences in neural underpinnings of PPI and PPF, and (iii) no data on neural underpinnings of PPI and PPF in other clinical disorders.Laura F. Naysmith is funded by Lido CTP Unilever, Biotechnology and Biological Sciences Research Council (BBSRC)

The Brain-Heart Connection: Establishment of a Novel Rodent Model of Focal Insular Ischemic Stroke to Examine the Pathophysiology of Stroke-Induced Heart Injury

The neurological influence of ischemic stroke in the generation of stroke-induced heart injury (SIHI) has been acknowledged for several years. However, pathophysiological mechanisms remain uncertain. Clinically, it is hypothesized that stroke involving the insular cortex (IC) initiates SIHI, since the IC controls autonomic regulation of cardiovascular function. Yet, given the high prevalence of shared risk factors between ischemic stroke and cardiovascular disorders, mechanistic conclusions from clinical studies are largely speculative. We therefore sought to establish a novel rodent model of focal insular ischemic stroke, used to evaluate chronic outcomes of SIHI. Focal ischemic stroke was induced into the right or left IC of male Wistar rats, through stereotaxic injection of endothelin-1. Control groups received an injection of ibotenic acid, phosphate-buffered saline or no injection. Before euthanasia, rats were assessed for autonomic deficits in sensorimotor gating. At 28 days post-injection, rats with left IC damage displayed trends of impaired sensorimotor gating; compared to rats with right IC damage and control groups. Pathologically, all injured groups exhibited a chronic increase in microglia activation, present at the IC and remote white/grey matter regions. Furthermore, these groups expressed left atrial cardiac fibrosis. When correlated, a positive association between microglia activation and cardiac fibrosis was observed. With this novel model, we have identified several downstream consequences of IC ischemic stroke within the brain and heart; affirming the focal contribution of IC damage to SIHI. Taken together, these results provide insight into potential mechanisms of post-stroke cardiac damage, serving as future therapeutic targets for SIHI

Developmentally vitamin D-deficient rats show enhanced prepulse inhibition after acute δ9-tetrahydrocannabinol

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD-deficient rats show selective cognitive deficits and novelty-induced hyperlocomotion and enhanced locomotor responses from acute treatment with psychomimetic drugs, such as amphetamine and MK-801. Here we aimed to examine the effect of a drug from a different class of psychomimetic/psychoactive compounds, Δ-tetrahydrocannabinol (THC), on tasks of relevance to the cognitive and positive symptoms of schizophrenia. The aim of this study was to investigate whether DVD deficiency modulates the behavioural effects of THC on tests of delay-dependent memory, sensorimotor gating and locomotion. Adult control and DVD-deficient rats were injected with THC (0, 0.3, 0.6, 1.25, 2.5 mg/kg) 15 min before a delay match to sample (DMTS) task using variable delays (0-24 s). A separate group of rats was injected with either 2.5 mg/kg THC or vehicle before tests of either prepulse inhibition (PPI) of the acoustic startle response or in the open field. Control and DVD-deficient rats showed a similar dose-dependent impairment in performance on the DMTS. The greatest impairment was observed at 2.5 mg/kg for all delays (0-24 s). DVD-deficient rats showed THC-induced enhancement of PPI, which was not observed in control rats. There was no effect of maternal diet on acoustic startle response or locomotor responses in the open field. This study reports the novel findings that DVD-deficient rats were more sensitive to the acute effects of THC on PPI. It appears that prenatal vitamin D deficiency has long-term effects on sensitivity to the behavioural effects of cannabinoids

An Analysis of Nicotine Exacerbation of Reductions in PPI in a Rodent Model of Schizophrenia.

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is known to be reduced when the dopamine D2 receptor is activated. We used a rodent model of psychosis in which increases in dopamine D2 receptor sensitivity are produced through neonatal quinpirole (a dopamine D2 / D3 agonist) treatment to rats. Rats were administered quinpirole (1mg/kg) or saline from postnatal day (P) 1-21. Rats were raised to adulthood and tested on PPI. Results showed that neonatal quinpirole treatment produced a significant reduction in PPI, and nicotine exacerbated this reduction. This reduction was partially blocked by the nicotinic antagonist mecamylamine. Brain tissue was analyzed for regulators of G-protein signaling (RGS) and results showed that neonatal quinpirole significantly decreased RGS9, but increased RGS17 as compared to controls. These results appear to indicate that the G-protein couples more efficiently to the D2 receptor, and nicotine exacerbates PPI deficits in D2 receptor-primed rats

Sensory processing in autism spectrum disorders and Fragile X syndrome-From the clinic to animal models.

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics

Nicotine has a Direct Effect on Brainstem Startle-Mediating Neurons

Individuals with schizophrenia have impairments in prepulse inhibition of startle (PPI) which correlates with cognitive deficits. Nicotine improves the performance of patients and healthy individuals with PPI deficits on PPI tests. We hypothesized that nicotine directly affect startle-mediating neurons of the caudal pontine recticular nucleus (PnC) of the brainstem using electrophysiological recordings. The data revealed that nicotine (10 pM) increases leak current amplitude, reduces membrane resistance, and depolarizes the resting membrane potential. Nicotine had no significant effect on the EPSC amplitude for neither the trigeminal nor auditory stimulations. All effects were reversed only by a high dose (10 pM) of the a-j nAChR antagonist MLA and a low dose of TMPH (lOOnM; antagonizes all but the a7 nAChR). The effect of nicotine persisted in the presence of cadmium (100 pM), which blocks synaptic transmission. These results confirm the functional expression of nAChRs in the PnC and suggest a role of nAChRs in modulating startle responses directly in the brainstem

An Experimental and Functional Neuroimaging Investigation into the Effects of Nicotine on Prepulse Inhibition of the Startle Reflex in Schizophrenia

Prepulse inhibition of the startle reflex (PPI) refers to the reduction of the startle response to a startling stimulus (pulse), when such a pulse is preceded by a stimulus of lower intensity (prepulse). PPI is believed to reflect the working of a sensory gating mechanism, which by limiting excess sensory input, protects information processing. PPI is impaired in psychiatric populations where such inhibitory processes are compromised, including schizophrenia. The excessive rate of smoking seen in people with schizophrenia is thought to reflect an attempt at self-medication. Nicotine increases PPI in animals as well as healthy humans, and combined such observations suggest the possibility that smoking may provide a way of restoring some of the cognitive abnormalities of schizophrenia as indexed by deficient PPI. This hypothesis was central to the investigations conducted as part of this thesis. The effects of nicotine on PPI were tested in people with schizophrenia and healthy controls. In the first study of its kind the neural correlates of the enhancing effect of nicotine on PPI were studied in both populations using functional magnetic resonance imaging. Similar motivational factors for smoking behaviour in healthy smokers were explored in a longitudinal study of smokers wishing to quit. Finally, a parallel study delved into the psychological significance of PPI by investigating the tenet that PPI reflects an automatic response, a quality particularly useful to schizophrenia research. Nicotine enhanced PPI in both healthy and schizophrenic subjects. Furthermore the neuroimaging data confirmed this modulatory effect to involve the hippocampus. Startle amplitude, but not PPI, during smoking was found to predict successful smoking cessation in healthy subjects. Finally, supporting evidence was found for the involuntary status of PPI. This thesis lends support to the hypothesis that smoking may represent an attempt to self-medicate symptoms in schizophrenia

Time course of the effects of lipopolysaccharide on prepulse inhibition and brain nitrite content in mice

AbstractThe systemic administration of lipopolysaccharide (LPS) induces time-dependent behavioral alterations, which are related to sickness behavior and depression. The time-course effects of LPS on prepulse inhibition (PPI) remain unknown. Furthermore, the time-dependent effects of LPS on central nitrite content had not been investigated. Therefore, we studied alterations induced by single LPS (0.5mg/kg, i.p.) administration to mice on parameters, such as PPI, depressive- and anxiety-like behaviors, working memory, locomotor activity and motor coordination, 1.5 and 24h post-LPS administration. IL-1β and TNFα in the blood and brain as well as brain nitrite levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). An overall hypolocomotion was observed 1.5h post-LPS, along with depressive-like behaviors and deficits in working memory. Increments in IL-1β content in plasma and PFC, TNFα in plasma and decreases in nitrite levels in the ST and PFC were also verified. Twenty-four hours post-LPS treatment, depressive-like behaviors and working memory deficits persisted, while PPI levels significantly reduced along with increases in IL-1β content in the PFC and a decrease in nitrite levels in the HC, ST and PFC. Our data demonstrate that a delayed increase (i.e., 24h post-LPS) in PPI levels ensue, which may be useful behavioral parameter for LPS-induced depression. A decrease in nitrergic neurotransmission was associated with these behavioral findings

Psychophysiological Markers of Vulnerability to Psychopathology in Men with an Extra X Chromosome (XXY)

Studying genetically defined syndromes associated with increased risk for psychopathology may help in understanding neurodevelopmental mechanisms related to risk for psychopathology. Klinefelter syndrome (47,XXY) is one of the most common sex chromosomal aneuploidies (1 in 650 male births) and associated with increased vulnerability for psychopathology, including psychotic symptoms. Yet, it remains unknown whether this increased risk is associated with underlying psychophysiological mechanisms that are typically deficient in individuals with psychotic disorders. The present study assessed three “classic” psychophysiological markers of psychosis in Klinefelter syndrome (KS): smooth pursuit eye movements (SPEM), prepulse inhibition (PPI) and P50 suppression. Fourteen adults with KS and 15 non-clinical adults participated in the study. Data on SPEM (reflecting visuo-motor control) as well as PPI and P50 suppression (reflecting sensory gating) were collected. Dysfunctions in SPEM were observed in individuals with KS, with less smooth pursuit as expressed in lower position gain. Also, reduced sensory gating in individuals with KS was suggested by significantly reduced prepulse inhibition of the startle response (PPI) (effect size 1.6). No abnormalities were found in suppression of the P50 (effect size 0.6). We speculate that impairments in these psychophysiological mechanisms may reflect core brain dysfunctions that may also mediate the described increased vulnerability for psychotic symptoms in KS. Although speculative, such deficit specific, rather than disorder specific, psychophysiological dysfunctions in KS might convey vulnerability to other types of psychopathology as well. As KS already can be diagnosed prenatally, the predictive value of childhood impairments in prepulse inhibition and smooth pursuit for development of psychopathology later in life could be assessed. In sum, studying individuals with KS may prove to be an avenue of research leading to new hypotheses and insights into “at risk” pathways to psychopathology

Epigenetic alterations at synaptic plasticity genes in a genetically heterogeneous rat model of neuropsychiatric disorders

Sensorimotor gating impairments are observed across a range of neuropsychiatric conditions. The prepulse inhibition of the acoustic startle response (PPI) is a validated measure of sensorimotor gating. Genetic and pharmacological manipulations in rodents have shown PPI is regulated by specific brain monoaminergic systems. Using genetically heterogeneous NIH-HS rats, we stratified individuals by %PPI. In low PPI animals, we observed elevated mRNA levels of certain neurotransmitter receptors, including metabotropic glutamate receptor Grm2, dopamine receptors Drd1 and Drd2, serotonin receptors Htr1a and Htr2a, and scaffolding protein Homer1, in the frontal cortex (FC) and striatum (STR). We found Drd2 mRNA levels were significantly increased in the low PPI group in STR. Multinomial regression analysis indicated Grm2 in FC and Grm2 and Drd2 in STR predicted PPI group. Additional studies showed a linear relationship between PPI and Grm2 in FC and Drd2 in STR. To explore possible epigenetic regulation of altered gene transcription, we adapted chromatin immunoprecipitation (ChIP) for novel application in frozen brain tissue. We evaluated abundance of acetylated histone H3 (H3ac) and trimethylation of lysine residue 27 of histone H3 (H3K27me3) at regions upstream of gene transcription start sites. No differences in levels of H3ac or H3K27me3 were observed. Studies assessing abundance of other histone modifications are warranted. These efforts may offer insight on how epigenetic modification leads to altered transcription of synaptic plasticity genes regulating sensorimotor gating observed in neuropsychiatric conditions