Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice.

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 GABAB receptors in the regulation of PPI of the startle reflex in mice.     

GABAergic projection from nucleus accumbens to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats

Previous studies have demonstrated that increased mesolimbic dopamine (DA) activity disrupts sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. Other behavioral changes following mesolimbic DA activation are mediated through GABAergic efferent projections from the nucleus accumbens (NAC) to the ventral pallidum (VP). In this experiment, we examined whether PPI deficits in rats following mesolimbic DA activation are mediated through these same GABAergic substrates. PPI was significantly disrupted in rats following infusion of DA (40 micrograms) into the NAC, and this effect was reversed by infusion of a low dose (10 ng) of the GABA agonist muscimol into the VP. In a second experiment, we tested the hypothesis and the loss of PPI following intra-NAC DA infusion results from a disruption of GABAergic activity within the VP. Consistent with this hypothesis, infusion of the GABA antagonist picrotoxin (0-0.2 micrograms) into the VP caused a significant loss of PPI. These findings strongly suggest that the accumbens-ventral pallidal GABAergic circuitry is a substrate for the decrease in sensorimotor gating induced by mesolimbic DA overactivity.     

Assessment of sensorimotor gating following selective lesions of cholinergic pedunculopontine neurons

Sensorimotor gating is the state‐dependent transfer of sensory information into a motor system. When this occurs at an early stage of the processing stream it enables stimuli to be filtered out or partially ignored, thereby reducing the demands placed on advanced systems. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the standard measure of sensorimotor gating. A brainstem–midbrain circuitry is widely viewed as mediating both PPI and ASR. In this circuitry, the pedunculopontine tegmental nucleus (PPTg) integrates sensory input and cortico‐basal ganglia output and, via presumed cholinergic signaling, inhibits ASR‐generating neurons within the reticular formation. Non‐selective damage to all neuronal types within PPTg reduces PPI. We assessed whether this effect originates in the loss of cholinergic signaling by examining ASR and PPI in rats bearing non‐selective (excitotoxic) or selective cholinergic (Dtx‐UII) lesions of PPTg. Excitotoxic lesions had no effect on ASR but reduced PPI at all prepulse levels tested. In contrast, selective depletion of cholinergic neurons reduced ASR to the extent that PPI was not measurable with standard (10–20 s) inter‐trial intervals. Subsequent testing revealed appreciable ASRs could be generated when the inter‐trial interval was increased (180 s). Under these conditions, PPI was assessed and no deficits were found after lesions of cholinergic PPTg neurons. These results show that cholinergic output from PPTg is essential for rapidly regenerating the ASR, but has no influence on PPI. Results are discussed in terms of sensorimotor integration circuitry and psychiatric disorders that feature disrupted ASR and PPI.     

Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats

The substantia nigra pars reticulata (SNR) is one of the major output nuclei of the basal ganglia. It connects the dorsal and ventral striatum with the thalamus, superior colliculus and pontomedullary brainstem. The SNR is therefore in a strategic position to regulate sensorimotor behavior. We here assessed the effects of SNR lesions on prepulse inhibition (PPI) of the acoustic startle response (ASR), stereotypy and locomotion in drug-free rats, as well as after systemic administration of the dopamine agonist DL-amphetamine (2 mg/kg), and the NMDA receptor antagonists dizocilpine (0.16 mg/kg) and CGP 40116 (2 mg/kg). SNR lesions reduced PPI, enhanced spontaneous sniffing and potentiated the locomotor stimulation by dizocilpine and CGP 40116. PPI was impaired by dizocilpine and CGP 40116 in controls. The ASR was enhanced in controls by dizocilpine and amphetamine. SNR lesions prevented the enhancement of the ASR by amphetamine. A second experiment tested the hypothesis that the SNR mediates PPI via a GABAergic inhibition of the startle pathway. Infusion of the GABA(B) antagonist phaclofen but not the GABA(A) antagonist picrotoxin into the caudal pontine reticular nucleus reduced PPI. Hence, lesion of the SNR reduces sensorimotor gating possibly by elimination of a nigroreticular GABAergic projection interacting with GABA(B) receptors. Moreover, destruction of the SNR enhances the motor stimulatory effects of amphetamine and of the NMDA antagonists dizocilpine and CGP 40116. We conclude that the SNR exerts a tonic GABAergic inhibition on sensorimotor behavior that is regulated by the dorsal and the ventral striatum.     

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

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 microg/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.     

Deep brain stimulation of the pedunculopontine tegmental nucleus modulates neuronal hyperactivity and enhanced beta oscillatory activity of the subthalamic nucleus in the rat 6-hydroxydopamine model

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) area has been introduced as a novel surgical therapy for dopamine refractory gait problems, freezing and postural instability in the late stage of Parkinson's disease (PD). Lesions of the pedunculopontine tegmental (PPTg) nucleus, the equivalent of the PPN in rodents, were shown to reduce the elevated discharge rate of the subthalamic nucleus (STN) in the 6-hydroxydopamine (6-OHDA) rat model of PD. In order to further elucidate the modulatory effect of the PPTg on the STN we examined the effect of 25 Hz low frequency PPTg stimulation on neuronal single unit activity and oscillatory local field potentials (LFPs) of the STN, and on the electrocorticogram (ECoG) of the primary motor cortex region in rats with unilateral 6-OHDA induced nigrostriatal lesions. Stimulation of the PPTg reduced the enhanced firing rate in the STN, without affecting the firing pattern or approximate entropy (ApEn). It also reduced the activity in the beta band (15-30 Hz) of the STN, which is elevated in 6-OHDA lesioned rats, without affecting beta activity in the motor cortex. We showed a modulatory effect of PPTg stimulation on altered neuronal STN activity in the PD 6-OHDA rat model, indicating that PPTg DBS may alter activity of the basal ganglia circuitry at least partially. It remains unclear, however, how these changes are exactly mediated and whether they are relevant with regard to the descending PPTg projections in the lower brainstem.     

Deep brain stimulation of the subthalamic nucleus in the 6-hydroxydopamine rat model of Parkinson's disease: effects on sensorimotor gating

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effectively used to treat motor symptoms in Parkinson's disease (PD). Recently more attention has been paid to behavioral disturbances caused by PD itself and by STN DBS. In the 6-hydroxydopamine (6-OHDA) PD rat model we investigated the effect of STN DBS on deficient prepulse inhibition (PPI) induced by the dopamine (DA) receptor agonist apomorphine, which is an operative measure for disturbed sensorimotor gating seen in certain neuropsychiatric disturbances. Male Sprague Dawley rats with bilateral lesions of the nigrostriatal DA system (striatal injection of 6-OHDA or vehicle for sham-lesion) were bilaterally implanted with electrodes for DBS into the STN. After determination of individual thresholds rats were stimulated (130Hz, 80μs pulse width) or sham-stimulated for epochs of six days. On the sixth day of each epoch rats were tested for PPI of the acoustic startle response after apomorphine or vehicle injection in a within randomized cross-over design. Stimulation of the STN improved PPI in vehicle-treated (control) rats, but deteriorated PPI after apomorphine treatment. This effect was more pronounced in sham-lesioned rats. Furthermore, in lesioned rats the startle reaction was marginally enhanced without effect of stimulation or apomorphine treatment. These data suggest that STN DBS interacts with dopaminergic action. With respect to functional neurosurgery, STN DBS alone may improve certain aspects of psychiatric disturbances, but may have a different impact when combined with dopaminergic medication.     

Rearrangement of the dendritic morphology of the neurons from prefrontal cortex and hippocampus after subthalamic lesion in Sprague–Dawley rats

Several studies in rodents have suggested the inactivation of the subthalamic nucleus (STN) as an alternative strategy to Parkinson's disease (PD) treatment. The STN is part of the basal ganglia and plays an important role in the motor function; however, recent data suggest that this structure has a critical role in the cognitive function of the limbic system. The STN receives direct projection from the prefrontal cortex (PFC), structure interconnected with the hippocampus and both structures send excitatory projections to the nucleus accumbens (NAcc). Here, we determined whether and which changes occurred 4 weeks after a STN lesion in the dendritic morphology of pyramidal neurons of the layers 3 and 5 of the PFC and basolateral amygdala, neurons of the ventral hippocampus, and the medium spiny neurons of the NAcc and caudate‐putamen. Dendritic morphology was measured using the Golgi‐Cox procedure followed by Sholl analysis. We also evaluated the effects of STN lesion on locomotor behavior assessed by an open field test, social interaction, acoustic startle response, prepulse inhibition, and locomotor activity induced by a novel environment and amphetamine. We found that STN damage induced a deficit in locomotion measured by open field test with neuronal hypertrophy in PFC (layer 5) and reduced spinogenesis in CA1 ventral hippocampus and PFC (layer 3). Taken together, these data suggest that the behavioral and morphological effects of STN lesion are, at least partially, mediated by limbic subregions with possible consequences for cognitive‐related behaviors observed in PD treatment. Synapse 68:114–126, 2014. © 2013 Wiley Periodicals, Inc.     

Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions in the nucleus accumbens core and shell subregions

The amplitude of the acoustic startle reflex is normally reduced when the startling stimulus is preceded by a weak click or ‘prepulse’. Prepulse inhibition (PPI) of acoustic startle has been used as an operational measure of sensorimotor gating or inhibition, and is reduced in schizophrenia patients and in rats with central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus offer a useful animal model to study impaired sensorimotor gating in schizophrenia. We have previously reported that DA-glutamate interactions in the nucleus accumbens (NAC) regulate PPI. The NAC has at least two major subregions — the core and shell — that have distinct anatomical and neurochemical properties. In this study, we compared changes in PPI after manipulations of DA-glutamate activity in these two NAC subregions. Consistent with previous findings, infusion of the non-NMDA agonist AMPA into the NAC core subregion significantly reduced PPI, and this effect was opposed by systemic administration of the D₂ antagonist haloperidol. Also consistent with previous reports, infusion of the non-NMDA antagonist CNQX into the NAC core subregion did not alter PPI, but its co-infusion with D-amphetamine (AMPH) attenuated the AMPH-disruption of PPI. In contrast, while PPI was reduced after AMPA infusion into the NAC shell subregion, this effect of AMPA could not be blocked by pretreatment with haloperidol. Infusion of either AMPHor CNQX into the NAC shell subregion reduced PPI independently. The PPI-disruptive effects of intra-shell CNQX infusion were not blocked by haloperidol. The present results suggest striking differences between the NAC core and shell subregions in their neurochemical modulation of sensorimotor gating of acoustic startle in the rat.     

Involvement of nucleus accumbens dopaminergic transmission in acoustic startle: observations concerning prepulse inhibition in rats with entorhinal cortex lesions

The relationship between the entorhinal cortex and prepulse inhibition (PPI) as well as the nucleus accumbens dopaminergic participation in acoustic startle were examined in rats. After the entorhinal cortex was damaged bilaterally using ibotenic acid, a microdialysis probe was placed in the nucleus accumbens for detection of dopamine before, during and after acoustic startle stimuli. In rats with bilateral entorhinal cortex lesions PPI was reduced, and extracellular dopamine in the nucleus accumbens was elevated with or without acoustic stimuli. The entorhinal cortex and the sensorimotor gating system thus may be related via dopaminergic connections in the nucleus accumbens, even though dopamine release did not coincide completely with acoustic startle stimuli.     

The effects of intra-accumbens neurotensin on sensorimotor gating

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine. Previous studies have shown that centrally administered neurotensin can modulate the activity of mesolimbic dopamine with a profile similar to neuroleptics. For example, infusions of neurotensin into the nucleus accumbens inhibit amphetamine-induced hyperlocomotion. Prepulse inhibition (PPI) occurs when a weak prestimulus (‘prepulse') inhibits the amplitude of the startle response to an intense stimulus (‘pulse'). PPI is an operational measure of sensorimotor gating which is strongly regulated by mesolimbic dopamine. This study examined the effects of various doses of neurotensin infused into the nucleus accumbens of rats on the prepulse inhibition (PPI) of their acoustic startle reflex. Neurotensin (0.25–5.0 μg) was infused into the nucleus accumbens of rats. Animals then received subcutaneous injections of amphetamine (2 mg/kg) or saline and were placed in startle chambers where measures of startle amplitude and PPI were obtained. Neurotensin increased baseline PPI and blocked amphetamine-induced disruption of PPI in a dose-dependent fashion. The lowest dose of neurotensin tested (0.25 μg) significantly increased baseline PPI and both 0.25 and 1.0 μg neurotensin blocked amphetamine-induced decreases in PPI. The 5.0 μg dose of neurotensin had no significant effect on prepulse inhibition. Neurotensin had no effect on the amplitude of the acoustic startle reflex in amphetamine- or saline-treated rats. The results suggest that intra-accumbens neurotensin has a significant, dose-dependent effect on sensorimotor gating in which lower doses (0.25–1.0 μg) exhibit a neuroleptic-like action.     

Investigation of the role of alpha‐2 adrenergic receptors on prepulse inhibition of acoustic startle reflex in rats

Objectives : Alpha‐2 adrenergic receptors target several behavioral functions. These receptors may connect with the brain pathways mediating sensorimotor gating system that associate with psychoses, and the literature that investigate the relationship between alpha‐2 receptors and sensorimotor gating system is very limited and some results are controversial. Thus, we aimed to investigate the role of alpha‐2 receptors on prepulse inhibition (PPI) of acoustic startle reflex which is a measure of sensorimotor gating. Experimental Design : Adult male Wistar rats were subjects. PPI was measured as the per cent inhibition of the startle reflex produced by a startling pulse stimulus. The average PPI levels were used in the further analyses. Clonidine (0.03–1 mg/kg), an agonist of alpha‐2 receptors, idazoxan (10 mg/kg), an antagonist alpha‐2 receptors, and saline were injected to rats intraperitoneally. PPI was evaluated at two different startle intensity levels (78 and 86 dB, respectively). Principal Observations : Treatments produced some significant changes on PPI of startle reflex at all two levels of startle intensity. While clonidine (0.06, 0.25, 0.5, and 1 mg/kg) disrupted significantly PPI, idazoxan (10 mg/kg) did not produce any significant effect on PPI. However, pretreatment with idazoxan reversed significantly clonidine‐induced disruption of PPI. Neither idazoxan (10 mg/kg) nor clonidine (1 mg/kg) produces any significant change on locomotor activity in naive rats. Conclusion : Because idazoxan and clonidine also act through imidazoline receptors, our results suggest that alpha‐2 and/or imidazoline receptors are associated with PPI of acoustic startle reflex in rats. Stimulation of these receptors may cause sensorimotor gating disturbances.     

Tactile, acoustic and vestibular systems sum to elicit the startle reflex

The startle reflex is elicited by intense tactile, acoustic or vestibular stimuli. Fast mechanoreceptors in each modality can respond to skin or head displacement. In each modality, stimulation of cranial nerves or primary sensory nuclei evokes startle-like responses. The most sensitive sites in rats are found in the ventral spinal trigeminal pathway, corresponding to inputs from the dorsal face. Cross-modal summation is stronger than intramodal temporal summation, suggesting that the convergence of acoustic, vestibular and tactile information is important for eliciting startle. This summation declines sharply if the cross-modal stimuli are not synchronous. Head impact stimuli activate trigeminal, acoustic and vestibular systems together, suggesting that the startle response protects the body from impact stimuli. In each primary sensory nucleus, large, second-order neurons project to pontine reticular formation giant neurons critical for the acoustic startle reflex. In vestibular nucleus sites, startle-like responses appear to be mediated mainly via the vestibulospinal tract, not the reticulospinal tract. Summation between vestibulospinal and reticulospinal pathways mediating startle is proposed to occur in the ventral spinal cord.     

Effects of neurotensin administered into the ventral tegmental area on prepulse inhibition of startle

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating. Both locomotor activity and PPI are regulated by mesolimbic dopamine activity. Neurotensin is a neuropeptide, which coexists with dopamine in mesolimbic neurons. Neurotensin receptors have been identified in the nucleus accumbens (NAC) and ventral tegmental area (VTA). Previous studies have shown that neurotensin administered into the NAC differentially modulates PPI and locomotor activity. In this study we tested the effects of neurotensin administered into the VTA on PPI and locomotor activity. Consistent with previous studies, intra-VTA administered neurotensin significantly increased spontaneous locomotor activity. However, intra-VTA administered neurotensin did not have any significant effect on PPI. These results suggest that PPI and locomotor activity may have dissociable mesolimbic substrates and that neurotensin in the VTA does not play an important role in regulating PPI.     

Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins

Post mortem, reduced brain reelin is noted in schizophrenia. Accordingly, the reelin-haploinsufficient heterozygous reeler mouse (HRM) has been posited as a murine model of the illness. One study reported that HRM exhibit deficits in prepulse inhibition (PPI) of the acoustic startle reflex, a sensorimotor-gating behavior that is disrupted in schizophrenia, although this finding has not been reproduced. To extend the characterization of putative sensorimotor-gating deficits in HRM, these mice were subjected to a sophisticated series of PPI tests. Mice were tested in a cross-modal PPI protocol that combined an acoustic prepulse with a tactile startle stimulus and also in a protocol that included varying prepulse–pulse intervals and varying acoustic startle pulse intensities. Levels of acoustic startle habituation and cross-modal PPI were significantly lower in HRM, although unimodal PPI did not differ. The HRM also exhibited increased PPI compared to wildtypes at short interstimulus intervals between prepulse and pulse stimuli when the interval between the acoustic prepulse and pulse were varied, and were more reactive to higher intensity startle stimuli. Some of these deficits in sensorimotor gating parallel those of schizophrenia, a disease characterized by alterations in synaptic protein expression. Therefore, levels of presynaptic proteins were measured in multiple brain regions using ELISA in HRM. No significant alterations in presynaptic protein expression were found. Thus, HRM exhibit a complex pattern of changes in startle reactivity and sensorimotor gating, with both similarities to and differences from schizophrenia. However, it is unlikely that these behavioral differences may be accounted for by altered regional levels of presynaptic proteins.     

The organization of the thalamocortical connections of the mediodorsal thalamic nucleus in the rat, related to the ventral forebrain-prefrontal cortex topography.

The medial and central segments of the mediodorsal nucleus of the thalamus (MD) receive afferents from the ventral forebrain, including the piriform cortex, the ventral pallidum, and the amygdaloid complex. Because MD is reciprocally interconnected with prefrontal and agranular insular cortical areas, it provides a relay of ventral forebrain activity to these cortical areas. However, there are also direct projections from the piriform cortex and the amygdala to the prefrontal and agranular insular cortices. This study addresses whether this system has a "triangular" organization, such that structures in the ventral forebrain project to interconnected areas in MD and the prefrontal/insular cortex. The thalamocortical projections of MD have been studied in experiments with injections of retrograde tracers into prefrontal or agranular insular cortical areas. In many of the same experiments, projections from the ventral forebrain to MD and to the prefrontal/insular cortex have been demonstrated with anterograde axonal tracers. The connections of the piriform cortex (PC) with MD and the prefrontal/insular cortex form an organized triangular system. The PC projections to the central and medial segments of MD and to the lateral orbital cortex (LO) and the ventral and posterior agranular insular cortices (AIv and AIp) are topographically organized, such that more caudal parts of PC tend to project more medially in MD and more caudally within the orbital/insular cortex. The central and medial portions of MD also send matching, topographically organized projections to LO, AIv and AIp, with more medial parts of MD projecting further caudally. The anterior cortical nucleus of the amygdala (COa) also projects to the dorsal part of the medial segment of MD and to its cortical targets, the medial orbital area (MO) and AIp. The projections of the basal/accessory basal amygdaloid nuclei to MD and to prefrontal cortex, and from MD to amygdaloceptive parts of prefrontal cortex, are not as tightly organized. Amygdalothalamic afferents in MD are concentrated in the dorsal half of the medial segment. Cells in this part of the nucleus project to the amygdaloceptive prelimbic area (PL) and AIp. However, other amygdaloceptive prefrontal areas are connected to parts of MD that do not receive fibers from the amygdala. Ventral pallidal afferents are distributed to all parts of the central and medial segments of MD, overlapping with the fibers from the amygdala and piriform cortex. Fibers from other parts of the pallidum, or related areas such as the substantia nigra, pars reticulata, terminate in the lateral and ventral parts of MD, where they overlap with inputs from the superior colliculus and other brainstem structures.(ABSTRACT TRUNCATED AT 400 WORDS)     

Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington''s disease.

The corpus striatum serves a critical function in inhibiting involuntary, intrusive movements. Striatal degeneration in Huntington's disease results in a loss of motor inhibition, manifested by abnormal involuntary choreiform movements. Sensorimotor inhibition, or "gating", can be measured in humans using the startle reflex: the startle reflex is normally inhibited when the startling stimulus is preceded 30-500 ms earlier by a weak prepulse. In the present study, prepulse inhibition (PPI) was measured in patients with Huntington's disease to quantify and characterise sensorimotor gating. Compared with age matched controls, patients with Huntington's disease exhibit less PPI. Startle gating deficits are evident in patients with Huntington's disease when startle is elicited by either acoustic or tactile stimuli. Even with stimuli that elicit maximal PPI in normal subjects, patients with Huntington's disease exhibit little or no PPI, and their pattern of startle gating does not show the normal modulatory effects usually elicited by changing the prepulse interval or intensity. Startle amplitude and habituation and latency facilitation are largely intact in these patients, although reflex latency is significantly slowed. In patients with Huntington's disease, startle reflex slowing correlates with cognitive impairment measured by the dementia rating scale, and with the performance disruptive effects of interference measured by the Stroop test. These findings document a profound disruption of sensorimotor gating in patients with Huntington's disease and are consistent with preclinical findings that identify the striatum and striatopallidal GABAergic efferent circuitry as critical substrates for sensorimotor gating of the startle reflex.     

The involvement of the mediodorsal nucleus of the thalamus and the midbrain extrapyramidal area in locomotion elicited from the ventral pallidum

Motor activity is regulated by projections from the nucleus accumbens to the ventral pallidum, but it is unclear which efferents regulate behavioral output from the ventral pallidum. Motor activity was elicited pharmacologically by microinjecting either the mu opioid receptor agonist, Tyr-D-Ala-Gly-NmePhe-Gly-OH (DAMGO) or the glutamate receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) into the ventral pallidum. The involvement of efferent projections was determined by microinjecting the local anesthetic procaine into the mediodorsal nucleus of the thalamus (MD) or the midbrain extrapyramidal area (MEA) prior to administering DAMGO or AMPA into the ventral pallidum. The motor activity induced by DAMGO was blocked by procaine microinjected into either the MD or the MEA. In contrast, procaine microinjected into the MD did not block motor activity elicited by AMPA while procaine into the MEA abolished the behavioral activation. These data indicate that the involvement of efferent projections from the ventral pallidum to either the MD or MEA in motor activation depends upon the type of receptor stimulated in the ventral pallidum.     

NMDA and non-NMDA antagonists infused into the nucleus reticularis pontis caudalis depress the acoustic startle reflex

The neural pathway that mediates the acoustic startle reflex has been proposed; however, the pharmacology underlying this reflex is less well known. The present study examined the role of excitatory amino acid receptors at the level of the nucleus reticularis pontis caudalis, a brainstem nucleus obligatory for the whole body startle reflex and implicated as the locus where extrinsic systems such as the amygdala may act to modulate acoustic startle. Twenty-nine rats, chronically implanted with bilateral cannulae aimed at the nucleus reticularis pontis caudalis, were tested to assess the effects of γ-d-glutamylglycine (DGG),dl-2-amino-5-phosphonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) on the amplitude of the acoustic startle reflex. Local infusion of each of the 3 compounds significantly reduced startle amplitude by as much as 70–80%. AP5 and CNQX attenuated startle over a dose range which indicated that the reticularis pontis caudalis may be much more sensitive to these compounds than other nuclei along the primary startle pathway. These results suggest that, at the level of the nucleus reticularis pontis caudalis, an excitatory amino acid neurotransmitter may mediate acoustic startle, and that both NMDA and non-NMDA receptor subtypes may be important for the expression of the acoustic startle reflex.     

Differential effects of dopamine agonists on acoustically and electrically elicited startle responses: comparison to effects of strychnine

This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to a spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.