Regulation of Prepulse Inhibition by Ventral Pallidal Projections
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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2019, Clinical NeurophysiologyCitation Excerpt :The PPN is the main structure within the first level of higher order hierarchical circuits governing the primary auditory startle circuit (Kofler et al., 2006). In rats, PPN lesions increase baseline startle reflex amplitude and abolish PPI without affecting long-term habituation (Swerdlow and Geyer, 1993b; Kodsi and Swerdlow, 1997). PPI is likely mediated by a cholinergic pathway, since direct injections of the cholinergic muscarinic antagonist scopolamine into the nucleus reticularis pontis caudalis in rats increased the basal startle reflex amplitude and reduced PPI (Fendt and Koch, 1999).