Sensory and sensorimotor gating deficits after neonatal ventral hippocampal lesions in rats.

Neonatal ventral hippocampal lesions (NVHLs) in rats lead to reduced prepulse inhibition (PPI) of startle and other behavioral deficits in adulthood that model abnormalities in schizophrenia patients. A neurophysiological deficit in schizophrenia patients and their first-degree relatives is reduced gating of the P50 event-related potential (ERP). N40 ERP gating in rats may be a cross-species analog of P50 gating, and is disrupted in experimental manipulations related to schizophrenia. Here, we tested whether N40 gating as well as PPI is disrupted after NVHLs, using contemporaneous measures of these two conceptually related phenomena. Male rat pups received sham or ibotenic acid NVHLs on postnatal day 7. PPI was tested on days 35 and 56, after which rats were equipped with cortical surface electrodes for ERP measurements. One week later, PPI and N40 gating were measured in a single test, using paired S1-S2 clicks spaced 500 ms apart to elicit N40 gating. Compared to sham-lesioned rats, those with NVHLs exhibited PPI deficits on days 35 and 56. NVHL rats also exhibited reduced N40 gating and reduced PPI, when measured contemporaneously at day 65. Deficits in PPI and N40 gating appeared most pronounced in rats with larger lesions, focused within the ventral hippocampus. In this first report of contemporaneous measures of two important schizophrenia-related phenotypes in NVHL rats, NVHLs reproduce both sensory (N40) and sensorimotor (PPI) gating deficits exhibited in schizophrenia. In this study, lesion effects were detected prior to pubertal onset, and were sustained well into adulthood.

Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats.

BACKGROUND: In rats, prepulse inhibition (PPI) of acoustic startle is disrupted by systemic administration of dopaminergic agonists, such as the dopamine D3 receptor (D3R)-preferential agonist pramipexole (PPX). PPX has D3R-active (S) and -inactive (R) stereoisomers. Here, we tested the neuroanatomical and stereochemical selectivity of PPX effects on PPI. METHODS: (S)-PRA or (R)-PRA (0, 0.47, 1.42, 4.73 µmol/kg) was injected sc 15 min prior to PPI testing in adult male Sprague Dawley rats. In separate rats, (S)-PPX (0, 3, 10 µg/0.5µl/side, ic) was infused into the nucleus accumbens (NAc), caudodorsal striatum (CS), or olfactory tubercle/Islands of Calleja (ICj) 15 min prior to PPI testing. D3R expression in these brain regions was assessed using quantitative rt-PCR. The PPI-disruptive effects of systemic (S)-PPX were also tested after pretreatment with the D3R-selective antagonist, U99194 (10mg/kg). RESULTS: Systemic administration of PPX stereoisomers demonstrated a dose-dependent effect of (S)-PPX on PPI, while (R)-PPX had no effect on PPI. PPX decreased PPI when infused into the NAc and ICj, but not the CS. Quantitative rt-PCR revealed D3R expression in ICj>NAc>CS. The PPI-disruptive effects of PPX were prevented by U99194. CONCLUSION: The PPI-reducing effects of PPX are stereospecific for the D3R-active (S)-isomer, neuroanatomically preferential for the D3R-rich ventral vs. D3R poor caudodorsal striatum, and prevented by pharmacologic D3R blockade. These findings are consistent with the conclusion that PPX disrupts PPI via stimulation of mesolimbic D3Rs.

Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats.

BACKGROUND: Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague-Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats. METHODS: The effects of APO (vehicle vs. 0.5 mg/kg) on PPI were tested in SD and LE rats in a within-subject design. Seven days later, under conditions mimicking PPI testing, half of the rats from each strain received either vehicle or APO (0.5 mg/kg) 20 min before euthanasia. NAC CREB and phospho-CREB levels were quantified from tissue sections reacted immunohistochemically. RESULTS: APO reduced PPI in both strains, with a significantly greater effect in SD vs. LE rats. APO also significantly reduced NAC core phospho-CREB levels in both strains, with a significantly greater effect in SD vs. LE rats. Among SD rats receiving APO, the reduction in NAC core CREB phosphorylation correlated significantly with the APO-induced reduction in PPI (R = 0.49). CONCLUSIONS: A dose of APO that disrupts PPI of acoustic startle causes a profound suppression of CREB phosphorylation in the NAC; both dopamine-sensitive behavioral and molecular phenotypes are more robust in SD vs. LE rats, and within SD rats, they are significantly correlated.

Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague-Dawley and Long-Evans rats.

RATIONALE: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague-Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60-120 ms) and less sensitive to their PPI-enhancing effects at short (10-30 ms), compared with Long-Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors. OBJECTIVE: The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats. METHODS: PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF). RESULTS: As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains. CONCLUSION: Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux.

Strain differences in the gating-disruptive effects of apomorphine: relationship to gene expression in nucleus accumbens signaling pathways.

BACKGROUND: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in certain psychiatric disorders, including schizophrenia. Sprague Dawley (SD) rats are more sensitive to PPI-disruptive effects of apomorphine (APO) at long interstimulus intervals (ISIs) (60-120 msec) and less sensitive to PPI-enhancing effects of APO at short ISIs (10-30 msec) compared with Long Evans (LE) rats. METHODS: Prepulse inhibition was tested in SD and LE rats after APO (.5 mg/kg) or vehicle in a within- subject design and sacrificed 14 days later. Total RNA was extracted from the nucleus accumbens (NAC). Approximately 700 dopamine-relevant transcripts on the Affymetrix 230 2.0 microarray were analyzed. RESULTS: As previously reported, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared with LE rats. One hundred four genes exhibited significantly different NAC expression levels in these two strains. Pathway analysis revealed that many of these genes contribute to dopamine receptor signaling, synaptic long-term potentiation, or inositol phosphate metabolism. The expression of some genes significantly correlated with measures of APO-induced PPI sensitivity in either SD or LE rats. The expression of select genes was validated by real-time reverse transcription polymerase chain reaction (RT-PCR). CONCLUSIONS: Differences in PPI APO sensitivity in SD versus LE rats are robust and reproducible and may be related to strain differences in the expression of genes that regulate signal transduction in the NAC. These genes could facilitate the identification of targets for ameliorating heritable gating deficits in brain disorders such as schizophrenia.

Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration.

BACKGROUND: Sprague Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to the disruption of prepulse inhibition (PPI) by systemically-administered dopamine (DA) agonists. This strain difference is heritable and insensitive to cross-fostering. Inherited differences in the ability of elevated DA activity to disrupt PPI may be useful for understanding the neural basis for PPI deficits in schizophrenia and other neuropsychiatric disorders. METHODS: PPI was tested in male SD and LE rats after amphetamine (AMPH) was administered: 1) subcutaneously (sc), or intra-cerebrally (ic) into 2) the nucleus accumbens core (NACc; medial or lateral subregions) or the NAC shell; 3) the anteromedial striatum (AMS) or 4) the posterior striatum (PS). RESULTS: SD and LE rats had comparable PPI levels after sc vehicle injection. PPI was disrupted in SD but not LE rats after sc AMPH injection. LE insensitivity to AMPH was confirmed after sc injection into non-pigmented dermis, demonstrating that it did not reflect melanocyte sequestration of AMPH. PPI was also disrupted in SD rats after ic infusion into the NACc (medial core: p<0.005; lateral core: p<0.001); in LE rats, these effects only approached threshold levels (medial core: p<0.06; lateral core: p<0.051). In SD rats, the highest dose of AMPH (40 microg) tended to reduce PPI after infusion into the AMS or PS, while in LE rats, this dose potentiated PPI after PS infusion. Comparisons of PPI in SD vs. LE rats revealed significant main effects of strain (SD>LE) after vehicle infusions into the NACc subregions and the PS. Comparisons of pre-infusion "matching" data, data from the first infusion day, and data from separate rats in a "mock-infusion" paradigm is consistent with the possibility that SD>LE PPI after ic vehicle infusion reflects the impact of restraint stress on PPI in LE rats. CONCLUSIONS: PPI is disrupted by AMPH administered sc or into the NACc in SD but not LE rats. Reduced PPI after ic vehicle infusion in LE vs. SD rats may reflect greater PPI-reducing effects of restraint stress in LE rats. The differential impact of restraint on PPI in SD vs. LE rats complicates the interpretation of strain differences in the effects of ic manipulations, but may provide an avenue for investigating the basis for differences in vulnerability to the gating-disruptive effects of stress.

The effects of apomorphine and D-amphetamine on striatal c-Fos expression in Sprague-Dawley and Long Evans rats and their F1 progeny.

We previously reported that Sprague-Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to disruption of prepulse inhibition (PPI) of the startle reflex by the dopamine agonists, apomorphine (APO) and D-amphetamine (AMPH). This susceptibility is inherited through F1 (SD x LE) and N2 backcross (F1 x SD) generations via an orderly pattern (SD>N2>F1>LE). Here we examined systemic APO (0.5 mg/kg) and AMPH (4.5 mg/kg) modulation of neural activity in four regions of the striatum suspected to be involved in the dopaminergic regulation of PPI - dorsolateral (dlCPu) and medial (mCPu) caudate/putamen and core (NACc) and medial shell (NACms) regions of nucleus accumbens - under conditions that mimicked those used to assess PPI. Immunohistochemical quantification of c-Fos protein expression was used as the surrogate measure of neural activity in SD and LE rats and their F1 crosses. Vehicle-treatment showed significant regional differences in Fos expression, particularly between the dlCPu and the other three areas, but no strain-related differences were observed. Three of four brain areas examined (dlCPu, mCPu and NACc) exhibited drug-induced changes in Fos expression--APO decreased and AMPH increased Fos expression in each region. The aggregate effect across these three regions revealed Fos expression to be significantly greater in LE compared to SD rats for both drugs, with F1 rats intermediate. This pattern of inheritance (LE>F1>SD) reveals an inverse relationship between striatal Fos expression and PPI sensitivity for these drugs; and a positive relationship with reported heritable differences in D2-linked G-protein binding in the CPu and NACc, and with locomotor activation/suppression by AMPH and APO.

Forebrain D1 function and sensorimotor gating in rats: effects of D1 blockade, frontal lesions and dopamine denervation.

Prefrontal D1 hypoactivity is implicated in the pathophysiology of schizophrenia, and might contribute to sensorimotor gating deficits in schizophrenia patients, based on evidence that D1 blockade in the medial prefrontal cortex (MPFC) reduces prepulse inhibition of startle (PPI) in animal models. PPI is disrupted by systemic and intra-MPFC infusion of the D1 antagonist, SCH23390. We investigated the role of the MPFC in the PPI-disruptive effects of systemic SCH23390 administration, and more generally, in the dopaminergic regulation of PPI. PPI was measured in rats after forebrain manipulations, including systemic administration of SCH23390, ibotenic acid lesions of the MPFC, and 6OHDA-induced dopamine (DA) depletion from MPFC or nucleus accumbens. Systemic SCH23390 disrupted PPI; these effects were not opposed by ibotenic acid lesions of the MPFC. PPI remained intact after MPFC DA depletion, but--as predicted by Bubser and Koch [M. Bubser, M. Koch, Prepulse inhibition of the acoustic startle response of rats is reduced by 6 hydroxydopamine lesions of the medial prefrontal cortex, Psychopharmacology 113 (1994) 487-492]--a reduction in PPI from pre- to post-surgery correlated significantly with MPFC DA loss. The effects of systemic SCH23390 were not opposed by NAC DA depletion. D1 receptors regulate PPI in rats, but this effect does not appear to be mediated either by the MPFC or by increased mesolimbic DA activity.

Reduced startle gating after D1 blockade: effects of concurrent D2 blockade.

BACKGROUND: Prefrontal D1 systems have been implicated in the regulation of working memory and in the pathophysiology of schizophrenia. D1 hypofunction might contribute to reduced sensorimotor gating in schizophrenia patients since D1 activity in the medial prefrontal cortex (MPFC) regulates prepulse inhibition of startle (PPI) in animal models. We studied the neurochemical basis for the D1 regulation of PPI in rats. METHODS: PPI to weak (1-5 dB over background) prepulses was measured after systemic or intra-MPFC administration of the D1 antagonist, SCH 23390, in rats pretreated systemically with the D2 antagonist, haloperidol (vehicle or 0.1 mg/kg). RESULTS: After vehicle pretreatment, systemic and intra-MPFC SCH 23390 disrupted PPI produced by weak prepulses. This effect was not significantly opposed by pretreatment with haloperidol (0.1 mg/kg). In contrast, the PPI-disruptive effects of the DA agonist amphetamine were significantly opposed by this dose of haloperidol. CONCLUSIONS: D1 blockade reduces PPI, but this effect does not appear to be mediated entirely via increased dopamine transmission at D2 receptors.

Organization of binaural excitatory and inhibitory inputs to the inferior colliculus from the superior olive.

The major excitatory, binaural inputs to the central nucleus of the inferior colliculus (ICC) are from two groups of neurons with different functions-the ipsilateral medial superior olive (MSO) and the contralateral lateral superior olive (LSO). A major inhibitory, binaural input emerges from glycinergic neurons in the ipsilateral LSO. To determine whether these inputs converge on the same postsynaptic targets in the ICC, two different anterograde tracers were injected in tonotopically matched areas of the MSO and the LSO on the opposite side in the same animal. The main findings were that the boutons from MSO axons terminated primarily in the central and caudal parts of the ICC laminae but that contralateral LSO terminals were concentrated more rostrally and on the ventral margins of the MSO inputs. In contrast, the ipsilateral LSO projection converged with the MSO inputs and was denser than the contralateral LSO projection. Consistent with this finding, retrograde transport experiments showed that the very low-frequency areas of the ICC with dense MSO inputs also received inputs from greater numbers of ipsilateral LSO neurons than from contralateral LSO neurons. The results suggest that different binaural pathways through the low-frequency ICC may be formed by the segregation of excitatory inputs to ICC from the MSO and the contralateral LSO. At the same time, the ipsilateral LSO is a major inhibitory influence in the target region of the MSO. These data support the concept that each frequency-band lamina in the ICC may comprise several functional modules with different combinations of inputs.