Elsevier

Brain Research

Volume 953, Issues 1–2, 25 October 2002, Pages 246-254
Brain Research

Research report
Startle gating in rats is disrupted by chemical inactivation but not D2 stimulation of the dorsomedial thalamus

https://doi.org/10.1016/S0006-8993(02)03298-5Get rights and content

Abstract

The neural regulation of sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle reflex, has been a focus of interest based on the consistent deficits in PPI reported in schizophrenia patients. While dorsomedial thalamus (MD) dysfunction has been implicated in the clinical ‘gating’ deficits of schizophrenia patients, relatively little is known regarding the regulation of PPI by the MD. We previously reported that PPI in rats is reduced after intra-MD infusion of the GABA agonist muscimol, or after excitotoxic lesions of the MD. In the present study, we tested the regulation of PPI by D2 receptors in the MD. PPI was measured after intra-MD infusion of the D2 agonist quinpirole (0, 1 or 10 μg/side) in a within-subject design. Infusion placement was confirmed functionally in later tests by reversible inactivation of the MD via intra-MD infusion of tetrodotoxin (TTX; 10 ng/side), and subsequently by direct histological examination. Intra-MD infusion of quinpirole had no significant effect on PPI, using doses that significantly disrupt PPI after infusion into the ventral forebrain (nucleus accumbens). TTX infusion into the MD caused a significant loss of PPI; this effect was not reversed by pretreatment with the atypical antipsychotic quetiapine (7.5 mg/kg). The MD regulation of PPI in rats is not mediated via D2 receptors, but is clearly manifested via PPI deficits after reversible MD inactivation via TTX.

Introduction

Converging evidence suggests that disturbances in mediodorsal thalamic nucleus (MD)-prefrontal cortex circuitry may play a critical role in the pathophysiology of schizophrenia. Imaging studies reveal reduced MD volume in subjects with chronic as well as first-episode schizophrenia [2], [8], [19], hypometabolism [8], [13], and lower concentrations of N-acetylaspartate, a putative marker of neuronal/axonal integrity [3], [15]. Postmortem studies describe reduced MD neuron number and volume [9], [19], [31], [35], and a 24% reduction in parvalbumin-immunoreactive varicosities in the middle layers of prefrontal cortex in schizophrenia, believed to reflect reduced input from MD [26].

One biological marker and potential endophenotype for schizophrenia is reduced prepulse inhibition (PPI) of startle. PPI is a measure of sensorimotor gating that occurs when a weak sensory event (the prepulse) inhibits or ‘gates’ the motor response to a subsequent startling stimulus. Relative to normal subjects, PPI is reduced in schizophrenia patients ( [5], cf. Ref. [7]), their first degree relatives [11] and in non-psychotic individuals with schizotypal personality disorder [10]. The loss of sensorimotor gating in schizophrenia is thought to reflect a genetically-based dysfunction within brain circuitry that regulates PPI [6].

Clinical evidence that the MD regulates gating of sensory phenomena comes from reports of vivid sensory disturbances and visual hallucinations after midline thalamic strokes [29], and activation of this region during hallucinations in schizophrenia patients [37]. Both animal and human studies provide more specific evidence that the MD regulates startle and PPI. PPI is reduced by MD lesions or infusion of the GABA agonist muscimol in rats [23], but not by MD infusion of the NMDA receptor antagonist dizocilpine [4]. In human PET studies, attentional modulation of PPI is associated with bilateral increases in MD glucose utilization [21]. One study reported a role of MD dopaminergic activity in the regulation of PPI [46], and in vitro studies suggest that the excitability of MD cells is sensitive to the D2 agonist quinpirole [24], which potently reduces PPI after systemic administration in rats (cf. Ref. [17]). In the present study, we assessed PPI in rats after manipulations of the MD, including: (1) D2 receptor activation via intra-MD infusion of the D2-family agonist quinpirole, and (2) chemical inactivation via intra-MD infusion of the Na+ channel inactivator, tetrodotoxin (TTX).

Section snippets

Material and methods

Thirty-eight naive male Sprague–Dawley rats (225–250 g; Harlan Laboratories, San Diego, CA, USA) were housed in groups of 2–3 and maintained on a reversed 12-h light, 12-h dark schedule (lights off at 07:00 h). All surgery and testing took place during the dark phase (09:00–16:00 h). Rats were handled within 48 h of arrival and regularly prior to any procedures to minimize stress, and were given ad libitum access to food and water except during surgery and behavioral testing. All efforts were

Results

Histological analysis revealed evidence of injector penetration into the MD complex, with a relatively limited distribution throughout the dorsal and central portions of this nucleus (Fig. 1A). Access to the MD invariably involved passage through the lateral habenula and stria medullaris of the thalamus, with some injector tips appearing to terminate at the ventral boundary of the habenula as shown in Fig. 1B. Some tissue necrosis was observed in virtually all rats, particularly in the cortical

Discussion

TTX inactivates cells by blocking voltage-dependent Na+ channels and thereby preventing membrane depolarization. Metabolic and histological studies confirm that TTX leads to temporary neuronal quiescence, with a subsequent return of function [16]. Neuronal inactivation via intracerebral infusion of TTX has been used to assess the behavioral function of several brain regions in the rat. For example, intracerebral infusion of TTX has been used to study behavioral consequences of temporary

Acknowledgements

This work was supported by NIMH Awards MH01436 and MH53484. The authors gratefully acknowledge the expert assistance of Morgan Munson and Pam Auerbach.

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