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ABSTRACT: Cognitive deficits represent a core symptom cluster in schizophrenia that are thought to reflect developmental dysregulations within a neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), and prefrontal cortex (PFC). The present experiments determined the cognitive effects of transiently inactivating VH in rats during a sensitive period of development. Neonatal (postnatal day 7, PD7) and adolescent (PD32) male rats received a single bilateral infusion of saline or tetrodotoxin (TTX) within the VH to transiently inactivate local circuitry and efferent outflow. Rats were tested as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire the first reversal and extra-dimensional shift (ED) stages. These impairments were age and region-specific as rats infused with TTX into the VH at PD32, or into the dorsal hippocampus at PD7, exhibited performance in the task similar to that of controls. Finally, acute systemic administration of the partial α7 nicotinic acetylcholine receptor (nAChR) agonist SSR 180711 (3.0 mg/kg) eliminated the TTX-induced performance deficits. Given that patients with schizophrenia exhibit hippocampal pathophysiology and deficits in the ED stages of set-shifting tasks, our results support the significance of transient hippocampal inactivation as an animal model for studying the cognitive impairments in schizophrenia as well as the pro-cognitive therapeutic potential of α7 nAChR agonists.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2012; 37(11):2476-86. · 6.99 Impact Factor
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ABSTRACT: These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic-cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic-basal forebrain-cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic-cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2011; 36(12):2477-87. · 6.99 Impact Factor
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ABSTRACT: Abnormal mesolimbic control of cortical cholinergic activity has been hypothesized to contribute to the cognitive symptoms of schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in prefrontal cortex (PFC), an activation thought to contribute to attentional processing. Thus, the effects of intra-NAC perfusion of NMDA (250-400 microM) on ACh release in PFC were determined in rats receiving lesions of the ventral hippocampus (VH) as neonates (nVHLX), a neurodevelopmental model of schizophrenia, or as adults (aVHLX). NMDA elevated ACh release (100-150% above baseline) in adults sham-lesioned as neonates or in aVHLX rats. Adult nVHLX were unresponsive to NAC NMDA receptor stimulation. The inability of nVHLX to respond to NMDA emerged over development as a separate experiment demonstrated that evoked ACh release was normal before puberty (100-150% increase) yet, in these same nVHLX animals, absent after puberty. Amphetamine-evoked ACh release was assessed in nVHLX animals to exclude potential limitations in release capacity. Amphetamine produced greater increases in ACh release than in shams, indicating that nVHLX does not impair the capacity of cholinergic neurons to release ACh. Finally, the ability of 13 days of pretreatment with clozapine (1.25 mg/kg/day) to reinstate NMDA-evoked cortical ACh efflux was determined. Clozapine treatment normalized NMDA-evoked ACh release in nVHLX animals. These experiments show that mesolimbic regulation of cortical ACh release is disrupted in postpubertal nVHLX rats and normalized by low-dose treatment of clozapine; supporting the usefulness of nVHLX animals for research on the neuronal mechanisms underlying the cognitive symptoms of schizophrenia.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2009; 34(13):2710-20. · 6.99 Impact Factor
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ABSTRACT: Glutamatergic and dopaminergic inputs converge on medium spiny neurons in nucleus accumbens and regulate the excitability of these projections to target areas including the cholinergic basal forebrain. NMDA receptors situated on these projections are locally modulated by D1- and D2-like receptors. We previously reported that the D1-like positive modulation of NMDA receptor activity is expressed trans-synaptically in the control of basal forebrain cholinergic projections to prefrontal cortex. The present experiments tested the hypothesis that D2-like receptors in accumbens negatively modulate cortical ACh release. Perfusion of NMDA (150 microM) into the shell region of the accumbens produced a sustained increase (150-200%) in ACh release in prefrontal cortex. This increase was completely blocked by co-perfusion with the D2-like agonist quinpirole (100 microM). Perfusion of quinpirole also reduced basal ACh release (approximately 50%) in prefrontal cortex. The contribution of D2 receptors to the quinpirole effect was assessed in two additional studies. The first study revealed that co-perfusion of the D2 antagonist haloperidol (100 microM) blocked the quinpirole-induced attenuation of NMDA mediated ACh release. The second experiment demonstrated that intra-accumbens perfusion of quinelorane (100 microM), a more selective D2 agonist than quinpirole, also attenuated the NMDA mediated ACh release. Collectively, these studies demonstrate that D2 receptors in accumbens negatively modulate basal and NMDA mediated increases in ACh release in prefrontal cortex. This negative modulation may contribute to the integration of normal attentional processing and goal directed behavior and to the therapeutic effects of antipsychotic medication on cognition in psychopathologies such as schizophrenia.
Neuropharmacology 10/2007; 53(3):455-63. · 4.81 Impact Factor
