Deciphering midbrain mechanisms underlying prepulse inhibition of startle

Fulcher, Niveen; Azzopardi, Erin; Oliveira, Cleusa De; Hudson, Roger; Schormans, Ashley L.; Zaman, Tariq; Allman, Brian L.; Laviolette, Steven R.; Schmid, Susanne

doi:10.1016/j.pneurobio.2019.101734

Cited by 30 publications

(24 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The EPM is a widely used assay to investigate anxiety/affective behavior in rodents (Walf and Frye, 2007;Schneider et al, 2011). The PPI of the startle is the reduction of the startle response when the startle stimulus is preceded by a subthreshold sensory stimulus (sensorimotor gating) (Koch and Schnitzler, 1997;Lauer et al, 2017;Fulcher et al, 2020). Impaired PPI of the startle has been demonstrated in patients with many neuropsychiatric and neurodevelopmental disorders, including schizophrenia and autism spectrum disorders (Takahashi and Kamio, 2018).…”

Section: Discussionmentioning

confidence: 99%

The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

Wang

Yang

et al. 2020

Front. Syst. Neurosci.

View full text Add to dashboard Cite

Background: In rodents, the period of increased vulnerability to the developmental effects of general anesthetics coincides with the period of age-specific organizing (masculinizing) effects of the major female sex hormone 17β-estradiol (E2) in the male brain and excitatory GABA type A receptor (GABA A R) signaling. We studied whether E2 synthesis and excitatory GABA A R signaling are involved in the mediation of the developmental effects of sevoflurane in male rats. Methods: Male Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na +-K +-2Cl − (NKCC1) Cl − importer, bumetanide, prior to sevoflurane exposure for 6 h on postnatal (P) day 4, P5, or P6. We tested whether a subsequent exposure of these rats to sevoflurane on P∼10 would cause electroencephalography (EEG)-detectable seizures. We also evaluated their behavior during the elevated plus maze (EPM) test on P∼60, prepulse inhibition (PPI) of acoustic startle responses on P∼70, and corticosterone secretion to physical restraint on P∼80. Results: The rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures (F (3 , 24) = 7.445, P = 0.001) and exhibited deficiencies during the EPM (F (3 , 55) = 4.397, P = 0.008) and PPI (F (3 , 110) = 5.222, P = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone (F (3 , 16) = 11.906, P < 0.001). These parameters in the sevoflurane-exposed rats that were pretreated with formestane or bumetanide were not different from those in the control rats.

show abstract

Section: Discussionmentioning

confidence: 99%

The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

Wang

Yang

et al. 2020

Front. Syst. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Sensorimotor gating deficits are a hallmark of many schizophrenia-like symptoms in CNS disorders. Dopaminergic neurons in the hypothalamus (Barrios et al, 2020), cholinergic or non-cholinergic pedunculopontine tegmental nucleus neurons in the midbrain (Fulcher et al, 2020), and D2 receptor-expressing neurons in the nucleus accumbens (Shilling et al, 2006;Berger et al, 2011;Yamaguchi et al, 2015) could also be involved in sensorimotor regulation, and the functional impairments caused by brain calcification might be responsible for the defects in Slc20a2-HO mice.…”

Section: Neurobehavioral Abnormalities and Their Relations With Brain Calcificationsmentioning

confidence: 99%

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Ren

Shen

et al. 2021

Front. Genet.

View full text Add to dashboard Cite

BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

show abstract

“…To do so, the photo-inhibition started with prepulse onset and lasted until the end of the interstimulus intervals (ISIs) between prepulse and pulse (Fig. 5a, right) [26][27][28][29]. Although photo-inhibition had no impact on pulse-alone stimulations interspersed with PPI trials (Fig.…”

Section: Optogenetic Inhibition Of Cea-pnc Excitatory Synapses Decreases Ppimentioning

confidence: 99%

“…Therefore, until recently, there was a consensus that PPI is mediated by cholinergic PPTg neurons inhibiting PnC giant neurons within the startle pathway. However, new optogenetic and chemogenetic rat studies clearly demonstrated that specific activation or inhibition of cholinergic PPTg neurons does not alter PPI [27][28][29][30]. Since the majority of neurons in the PPTg are non-cholinergic [31], it is currently suggested that PPI may be a function of GABAergic and/or glutamatergic cells in the PPTg and/or another structure directly projecting to the PnC.…”

Section: Introductionmentioning

confidence: 99%

The amygdala modulates prepulse inhibition of the auditory startle reflex through excitatory inputs to the caudal pontine reticular nucleus

2021

View full text Add to dashboard Cite

Background Sensorimotor gating is a fundamental pre-attentive process that is defined as the inhibition of a motor response by a sensory event. Sensorimotor gating, commonly measured using the prepulse inhibition (PPI) of the auditory startle reflex task, is impaired in patients suffering from various neurological and psychiatric disorders. PPI deficits are a hallmark of schizophrenia, and they are often associated with attention and other cognitive impairments. Although the reversal of PPI deficits in animal models is widely used in pre-clinical research for antipsychotic drug screening, the neurotransmitter systems and synaptic mechanisms underlying PPI are still not resolved, even under physiological conditions. Recent evidence ruled out the longstanding hypothesis that PPI is mediated by midbrain cholinergic inputs to the caudal pontine reticular nucleus (PnC). Instead, glutamatergic, glycinergic, and GABAergic inhibitory mechanisms are now suggested to be crucial for PPI, at the PnC level. Since amygdalar dysfunctions alter PPI and are common to pathologies displaying sensorimotor gating deficits, the present study was designed to test that direct projections to the PnC originating from the amygdala contribute to PPI. Results Using wild type and transgenic mice expressing eGFP under the control of the glycine transporter type 2 promoter (GlyT2-eGFP mice), we first employed tract-tracing, morphological reconstructions, and immunohistochemical analyses to demonstrate that the central nucleus of the amygdala (CeA) sends glutamatergic inputs lateroventrally to PnC neurons, including GlyT2+ cells. Then, we showed the contribution of the CeA-PnC excitatory synapses to PPI in vivo by demonstrating that optogenetic inhibition of this connection decreases PPI, and optogenetic activation induces partial PPI. Finally, in GlyT2-Cre mice, whole-cell recordings of GlyT2+ PnC neurons in vitro paired with optogenetic stimulation of CeA fibers, as well as photo-inhibition of GlyT2+ PnC neurons in vivo, allowed us to implicate GlyT2+ neurons in the PPI pathway. Conclusions Our results uncover a feedforward inhibitory mechanism within the brainstem startle circuit by which amygdalar glutamatergic inputs and GlyT2+ PnC neurons contribute to PPI. We are providing new insights to the clinically relevant theoretical construct of PPI, which is disrupted in various neuropsychiatric and neurological diseases.

show abstract

Deciphering midbrain mechanisms underlying prepulse inhibition of startle

Cited by 30 publications

References 84 publications

The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

The amygdala modulates prepulse inhibition of the auditory startle reflex through excitatory inputs to the caudal pontine reticular nucleus

Contact Info

Product

Resources

About