Regulation of Prepulse Inhibition by Ventral Pallidal Projections

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Abstract

The acoustic startle reflex is inhibited by the presentation of a weak auditory prestimulus 30–500 ms prior to the startling stimulus. Previous studies have demonstrated that prepulse inhibition (PPI) of acoustic startle is regulated by GABAergic activity in the ventral pallidum. Ventral pallidal efferents include major projections to the pedunculopontine tegmental nucleus (PPTg), subthalamic nucleus (STN), and mediodorsal thalamus (MD). We used lesion and intracerebral infusion techniques to determine the relevance of these projections to the ventral pallidal regulation of PPI. Consistent with previous results, PPTg lesions significantly reduced PPI in all startle sessions, while MD lesions significantly reduced PPI only under certain experimental conditions. STN lesions failed to alter PPI, but they did significantly disrupt amphetamine-induced locomotion, verifying the behavioral effectiveness of these lesions. Infusion of the GABA-A agonist muscimol into either the PPTg or the MD significantly reduced PPI. Ventral pallidal projections to the PPTg and to the MD thus appear to regulate PPI, possibly via a GABAergic mechanism. Pallidal projections to the STN may regulate other behavioral processes such as locomotor activity, but they do not appear to regulate sensorimotor gating of the acoustic startle reflex.

Introduction

The acoustic startle reflex has been used to measure sensorimotor gating in a variety of human [3, 5, 29, 32, 35] and animal [6, 11, 18, 19, 30, 31, 37] studies. The contraction of whole-body musculature in response to a loud auditory stimulus is inhibited by a weak auditory prepulse presented 30–500 ms prior to the startling stimulus [[12]]. This prepulse inhibition (PPI) of acoustic startle is used as an operational measure of sensorimotor gating. PPI is significantly reduced in patients whose symptoms may be due to deficient central inhibition of sensory, motor, or cognitive information, including individuals with schizophrenia [3, 32], Huntington's Disease [[35]], or obsessive compulsive disorder [[29]]. Because these disorders have been associated with pathology in both the basal ganglia [2, 4, 24] and corticostriatal connections [[8]], attempts to elucidate the neural substrates of sensorimotor gating have focused on striatal circuitry [18, 19, 30].

While prepulse inhibition of the startle reflex appears to be mediated at or below the pons, PPI is regulated by forebrain circuitry, including both the ventral [18, 19, 30, 31] and the caudodorsal striatum [[19]]. Dopaminergic hyperactivity in the ventral striatal nucleus accumbens (NAcc) significantly reduces PPI in rats [[31]]. This NAcc regulation of PPI appears to be mediated by GABAergic projections to the ventral pallidum (VP). The PPI disruptive effects of either intra-NAcc dopamine infusion or excitotoxic NAcc lesions are reversed by intra-VP infusion of the GABA agonist muscimol [18, 30] and are mimicked by intra-VP infusion of the GABA antagonist picrotoxin [19, 20, 30, 33]. Thus, GABAergic activity in the VP clearly regulates PPI: reductions in VP GABAergic activity result in a reduction in PPI, while increases in VP GABAergic activity reverse the PPI disruptive effects of NAcc dopamine activation or NAcc cell lesions.

Ventral pallidal regulation of PPI might be mediated by one or many VP efferent pathways. The pallidal projections to the pedunculopontine tegmental nucleus (PPTg) provide a direct link between the VP and the primary startle circuit [17, 22, 25, 28, 39]. VP efferents to the mediodorsal thalamus (MD) form the pallidothalamic component of the limbic “corticostriato-pallidothalamic” (CSPT) loop, and VP projections to the subthalamic nucleus (STN) contribute to the “indirect” pathway of descending basal ganglia circuitry [[1]].

Recent studies have shown that PPTg lesions significantly reduce PPI [17, 33]. Because the PPTg projects directly to the nucleus reticularis pontis caudalis (NRPC)—an integral component of the startle reflex pathway [10, 21]—forebrain regulation of PPI might be mediated via a NAcc-VP-PPTg-NRPC circuit. However, both the STN and the MD are intimately involved in motor and cognitive processes [16, 23, 34], so pallidal projections to either of these structures might also modulate PPI. In the present study, we used lesion and intracerebral drug infusion techniques to more completely assess PPI regulation by VP projections to the STN, MD, and PPTg.

Section snippets

Animals

A total of seventy-eight Male Sprague-Dawley rats (225–250 g; Harlan, Indianapolis, IN) were housed in groups of two or three and maintained on a reverse 12 h/12 h light/dark schedule (lights off at 0700 h) with food and water provided ad lib. Behavioral testing occurred between 0900 and 1500 h, during the dark phase, when acoustic startle is most robust and least variable [[9]]. Animals were handled individually within 3 days of arrival and daily thereafter.

Surgery

All surgery occurred on the eighth

Changes in PPI After Manipulations of the Pedunculopontine Tegmental Nucleus

As previously reported, lesions of the pedunculopontine tegmental nucleus (PPTg) significantly reduced PPI; in the present study, these lesions did not significantly alter other startle variables. ANOVA revealed that quinolinic acid lesions of the PPTg did not significantly alter startle amplitude, F(1, 14) < 1, NS, or peak startle latency, F(1, 14) < 1, NS. There was, however, a significant effect of trial type on latency, F(7, 98) = 3.76, p < 0.005, with no lesion × trial type interaction, F

Discussion

Prepulse inhibition of acoustic startle was significantly reduced by quinolinic acid (QA) lesions of the pedunculopontine tegmental nucleus (PPTg) and—under certain conditions—the mediodorsal thalamic nucleus (MD), but not by lesions of the subthalamic nucleus (STN). Infusion of the GABA-A agonist muscimol into the PPTg or MD dose dependently reduced PPI. The present findings suggest the possibility that the pallidal regulation of PPI is mediated via GABAergic outflow, involving

Acknowledgements

The authors gratefully acknowledge the excellent assistance of Mr. Navid Taaid, Mr. Daniel Zisook, Ms. Heidi Hartston, and Mrs. Pamela Auerbach for their contributions to data acquisition and to construction of this manuscript. N.R.S. is supported by NIMH 48381 and NIMH 42228, while M.H.K. is supported by the Lucille P. Markey Charitable Trust. Methods described in this study are identical to those used in similar studies and thus descriptions of these methods closely resemble previously

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