Neural Circuits Containing Pallidotegmental GABAergic Neurons are Involved in the Prepulse Inhibition of the Startle Reflex in Mice

doi:10.1016/j.biopsych.2006.06.035

Biological Psychiatry

Volume 62, Issue 2, 15 July 2007, Pages 148-157

https://doi.org/10.1016/j.biopsych.2006.06.035 Get rights and content

Background

Prepulse inhibition (PPI) of the startle response is a measure of the inhibitory function and time-linked information processing by which a weak sensory stimulus (the prepulse) inhibits the startle response caused by a sudden intense stimulus. We attempted to clarify the neuronal circuits underlying the control of PPI of the startle reflex in mice.

Methods

c-Fos immunohistochemistry was used to detect neurons activated by startle pulse and/or prepulse trials. Behavioural pharmacology and tracing studies were also conducted.

Results

The lateral globus pallidus (LGP) was activated by prepulses. Activation of the caudal pontine reticular nucleus (PnC) evoked by the startle pulses was inhibited under PPI conditions. Double-immunostaining revealed that c-Fos-positive cells in the LGP following prepulse trials were GABAergic neurons. Bilateral microinjections of lidocaine into the LGP resulted in an impairment of PPI. Fluoro-gold infusion into the PnC and the pedunculopontine tegmental nucleus (PPTg) retrogradely labeled neurons in the PPTg and LGP, respectively. Microinjections of phaclofen into the PPTg significantly impaired PPI.

Conclusions

These results suggest that GABAergic neurons in the LGP which project to the PPTg play a crucial role through the activation of GABA_B receptors in the regulation of PPI of the startle reflex in mice.

Section snippets

Animals

Male ICR mice (Nihon SLC Co, Shizuoka, Japan) that were 8 weeks old at the beginning of the experiments were used. The animals were housed in plastic cages and kept in a regulated environment (23 ± 1°C, 50 ± 5% humidity), with a 12/12 h light-dark cycle (lights on at 9:00 AM). Food (Labo MR Stock, Nihon Nosan Kogyou Inc, Kanagawa, Japan) and tap water were available ad libitum.

All animal care and use were in accordance with the National Institutes of Health Guide for the Care and Use of

Prepulse Inhibition of Acoustic Startle Response

Figure 1 shows the effect of a prepulse on the acoustic startle reflex in mice. Mice were exposed to either no stimulus (control group, n = 5), a startle stimulus without a prepulse (startle group, n = 8), a startle stimulus with a prepulse (PPI group, n = 7) or a prepulse without a startle stimulus (prepulse group, n = 6). Statistical analysis revealed a significant effect of group [F(3,22) = 11.056, p < .001]. Post-hoc analysis indicated a significant increase in the startle amplitude in the

Discussion

The fast excitatory pathway of the acoustic startle system involves serial connections linking the auditory nerve, cochlear root neurons, PnC and spinal motor neurons (Lee et al. 1996). In the present study, we found that a startle pulse stimulus increased c-Fos expression in the PnC, which was attenuated by a weak prepulse before the pulse stimulus. Consistent with this finding, previous studies have demonstrated that PnC neurons are markedly inhibited by an acoustic prepulse in mice (Carlson

References (56)

T. Bast et al.
Hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus and the effects of pretreatment with haloperidol and clozapine
Neuroscience
(2001)
F.X. Castellanos et al.
Sensorimotor gating in boys with Tourette’s syndrome and ADHD
Biol Psychiatry
(1996)
S.C. Dulawa et al.
Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice
Neuropharmacology
(2000)
B.A. Ellenbroek et al.
Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex
Neuroscience
(1996)
R.L. Fradley et al.
STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating
Behav Brain Res
(2005)
M.A. Geyer et al.
Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia
Biol Psychiatry
(1993)
S. Hart et al.
Localizing haloperidol effects on sensorimotor gating in a predictive model of antipsychotic potency
Pharmacol Biochem Behav
(1998)
J. He et al.
A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats
Neuropsychopharmacology
(2002)
T. Herdegen et al.
Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins
Brain Res Rev
(1998)
M. Koch et al.
Role of the substantia nigra pars reticulate in sensorimotor gating, measured by prepulse inhibition of startle in rats
Behav Brain Res
(2000)

M.H. Kodsi et al.

Ventral pallidal GABA-A receptors regulate prepulse inhibition of acoustic startle

Brain Res

(1995)

M.H. Kodsi et al.

Regulation of prepulse inhibition by ventral pallidal projections

Brain Res Bull

(1997)

B.D. Kretschmer et al.

The ventral pallidum mediates disruption of prepulse inhibition of the acoustic startle response induced by dopamine agonist, but not by NMDA antagonists

Brain Res

(1998)

L. Li et al.

Effects of bilateral electrical stimulation of the ventral pallidum on acoustic startle

Brain Res

(1999)

L. Li et al.

Using intracranial electrical stimulation to study the timing of prepulse inhibition of the startle reflex

Brain Res Prot

(2000)

T. Moriizumi et al.

Separate neuronal populations of the rat globus pallidus projecting to the subthalamic nucleus, auditory cortex and pedunculopontine tegmental area

Neuroscience

(1992)

K. Saitoh et al.

Possible role of the brainstem in the mediation of prepulse inhibition in the rat

Neurosci Lett

(1987)

J.M. Shoemaker et al.

Prefrontal D1 and ventral hippocampal N-methyl-D-aspartate regulation of startle gating in rats

Neuroscience

(2005)

T.E. Sipes et al.

DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum

Brain Res

(1997)

N.R. Swerdlow et al.

A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder

Biol Psychiatry

(1993)

N.R. Swerdlow et al.

Regulation of sensorimotor gating in rats by hippocampal NMDA: anatomical localization

Brain Res

(2001)

N.R. Swerdlow et al.

Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists

Pharmcol Biochem Behav

(2005)

W.T. Zhang et al.

Prepulse inhibition in rats with temporary inhibition/inactivation of ventral or dorsal hippocampus

Pharmacol Biochem Behav

(2002)

V.P. Bakshi et al.

Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response

J Pharmacol Exp Ther

(1994)

D. Braff et al.

Prestimulus effects on human startle reflex in normals and schizophrenics

Psychophysiology

(1978)

D.L. Braff et al.

Sensorimotor gating and schizophrenia: human and animal model studies

Arch Gen Psychiatry

(1990)

S.B. Caine et al.

Behavioral effect of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: locomotion, cocaine self-administration, and prepulse inhibition of startle

Behav Neurosci

(2001)

S. Carlson et al.

Caudal pontine reticular formation of C57BL/6J mice: response to startle stimuli, inhibition by tones and plasticity

J Neurophysiol

(1998)

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Citation Excerpt :
Deficits in prepulse inhibition are observed in patients suffering from certain neuropsychiatric disorders, including schizophrenia (Braff et al., 1978; Castellanos et al., 1996). Prepulse inhibition deficits in schizophrenia can be mimicked in rodents by MK-801 treatment (Arai et al., 2008; Takahashi et al., 2007). The effects of fasudil on MK-801-induced prepulse inhibition deficits were statistically significant based on the result of three-way ANOVA with repeated measures (Fig. 5A).
Current antipsychotics used to treat schizophrenia have associated problems, including serious side effects and treatment resistance. We recently identified a significant association of schizophrenia with exonic copy number variations in the Rho GTPase activating protein 10 (ARHGAP10) gene using genome-wide analysis. ARHGAP10 encodes a RhoGAP superfamily member that is involved in small GTPase signaling. In mice, Arhgap10 gene variations result in RhoA/Rho-kinase pathway activation. We evaluated the pharmacokinetics of fasudil and hydroxyfasudil using liquid chromatography-tandem mass spectrometry in mice. The antipsychotic effects of fasudil on hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits were also investigated in a MK-801-treated pharmacological mouse schizophrenia model. Fasudil and its major metabolite, hydroxyfasudil, were detected in the brain at concentrations above their respective K_i values for Rho-kinase after intraperitoneal injection of 10 mg kg⁻¹ fasudil. Fasudil improved the hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits in MK-801-treated mice in a dose-dependent manner. Following oral administration of fasudil, brain hydroxyfasudil was detected at concentration above the K_i value for Rho-kinase whilst fasudil was undetectable. MK-801-induced hyperlocomotion was also improved by oral fasudil administration. These results suggest that fasudil has antipsychotic-like effects on the MK-801-treated pharmacological mouse schizophrenia model. There are two isoforms in Rho-kinase, and further investigation is needed to clarify the isoforms involved in the antipsychotic-like effects of fasudil in the MK-801-treated mouse schizophrenia model.
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Reelin, a large extracellular matrix protein, helps to regulate neuronal plasticity and cognitive function. Several studies have shown that Reelin dysfunction, resulting from factors such as mutations in gene RELN or low Reelin expression, is associated with schizophrenia (SCZ). We previously reported that microinjection of Reelin into cerebral ventricle prevents phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear whether and how Reelin ameliorates behavioral abnormalities in the animal model of SCZ. In the present study, we evaluated the effect of recombinant Reelin microinjection into the medial prefrontal cortex (mPFC) on abnormal behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Microinjection of Reelin into the mPFC prevented impairment of recognition memory of MK-801-treated mice in the novel object recognition test (NORT). On the other hand, the same treatment had no effect on deficits in sensory-motor gating and short-term memory in the pre-pulse inhibition and Y-maze tests, respectively. To establish the neural substrates that respond to Reelin, the number of c-Fos-positive cells in the mPFC was determined. A significant increase in c-Fos-positive cells in the mPFC of MK-801-treated mice was observed when compared with saline-treated mice, and this change was suppressed by microinjection of Reelin into the mPFC. A K2360/2467A Reelin that cannot bind to its receptor failed to ameliorate MK-801-induced cognitive deficits in NORT. These results suggest that Reelin prevents MK-801-induced recognition memory impairment by acting on its receptors to suppress neural activity in the mPFC of mice.
Muscimol injection into the substantia nigra but not globus pallidus affects prepulse inhibition and startle reflex.
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Behavioral arrest is an essential feature of an animal's survival. Acoustic startle reflex (ASR) is an involuntary whole-body contraction of the skeletal musculature to an unexpected auditory stimulus. This strong reaction can be decreased by prepulse inhibition (PPI) phenomenon; which, for example, is important in reducing distraction during the processing of sensory input. Several brainstem regions are involved in the PPI and startle reflex, but a previous study from our laboratory showed that the main input structure of Basal Ganglia (BG) – the striatum – modulates PPI. The pallidum and nigra are connected with striatum and these brainstem structures. Here, we investigated the role of these striatum outputs in the brain regions on startle amplitude, PPI regulation, and exploratory behavior in Wistar rats. The temporary bilateral inhibition of the globus pallidus (GP) by muscimol lead to motor impairment, without disturbing startle amplitude or PPI. Similarly, inhibition of the entopeduncular nucleus (EPN) specifically disrupted the exploratory behavior. On the other hand, the substantia nigra reticulata (SNr) inhibition interfered in all measured behaviors: decreased the PPI percentage, increased ASR and impaired the locomotor activity. The nigra is a key BG output structure which projects to the thalamus and brainstem. These findings extend our previous study showing that the striatum neurons expressing D1 receptors involvement in PPI occurs via the direct pathway to SNr, but not to the pallidum which more likely occurs by its connection with the caudal pontine nucleus, superior colliculus and/or pedunculopontine nucleus pivotal structures for startle reflex modulation.
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Perinatal virus infection is an environmental risk factor for neurodevelopmental disorders such as schizophrenia. We previously demonstrated that neonatal treatment with a viral mimetic, polyriboinosinic-polyribocytidilic acid (polyI:C), in mice leads to emotional and cognitive deficits in adolescence. Here, we investigated the effects of antipsychotics on polyI:C-induced behavioral abnormalities. We also performed a proteomic analysis in the hippocampus of polyI:C-treated adult mice using two-dimensional electrophoresis to understand the changes in protein expression following neonatal immune activation. Neonatal mice were subcutaneously injected with polyI:C for 5 days (postnatal day 2–6). At 10 weeks, sensorimotor gating, emotional and cognitive function were analyzed in behavioral tests. Clozapine improved PPI deficit and emotional and cognitive dysfunction in polyI:C-treated mice. However, haloperidol improved only PPI deficit. Proteomic analysis revealed that two candidate proteins were obtained in the hippocampus of polyI:C-treated mice, including aldehyde dehydrogenase family 1 member L1 (ALDH1L1) and collapsin response mediator protein 5 (CRMP5). These data suggest that the neonatal polyI:C-treated mouse model may be useful for evaluating antipsychotic activity of compounds. Moreover, changes in the protein expression of ALDH1L1 and CRMP5 support our previous findings that astrocyte-neuron interaction plays a role in the pathophysiology of neurodevelopmental disorders induced by neonatal immune activation.

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Original ArticleNeural Circuits Containing Pallidotegmental GABAergic Neurons are Involved in the Prepulse Inhibition of the Startle Reflex in Mice

Background

Methods

Results

Conclusions

Section snippets

Animals

Prepulse Inhibition of Acoustic Startle Response

Discussion

Neuroscience

Biol Psychiatry

Neuropharmacology

Neuroscience

Behav Brain Res

Biol Psychiatry

Pharmacol Biochem Behav

Neuropsychopharmacology

Brain Res Rev

Behav Brain Res

Brain Res

Brain Res Bull

Brain Res

Brain Res

Brain Res Prot

Neuroscience

Neurosci Lett

Neuroscience

Brain Res

Biol Psychiatry

Brain Res

Pharmcol Biochem Behav

Pharmacol Biochem Behav

Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response

J Pharmacol Exp Ther

Prestimulus effects on human startle reflex in normals and schizophrenics

Psychophysiology

Sensorimotor gating and schizophrenia: human and animal model studies

Arch Gen Psychiatry

Behavioral effect of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: locomotion, cocaine self-administration, and prepulse inhibition of startle

Behav Neurosci

Caudal pontine reticular formation of C57BL/6J mice: response to startle stimuli, inhibition by tones and plasticity

J Neurophysiol

Original Article
Neural Circuits Containing Pallidotegmental GABAergic Neurons are Involved in the Prepulse Inhibition of the Startle Reflex in Mice