Transient inactivation of the neonatal ventral hippocampus impairs attentional set-shifting behavior: reversal with an α7 nicotinic agonist

TY - JOUR

T1 - Transient inactivation of the neonatal ventral hippocampus impairs attentional set-shifting behavior

T2 - reversal with an α7 nicotinic agonist

AU - Brooks, Julie M

AU - Pershing, Michelle L

AU - Thomsen, Morten Skøtt

AU - Mikkelsen, Jens D

AU - Sarter, Martin

AU - Bruno, John P

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - Age Factors

KW - Analysis of Variance

KW - Anesthetics, Local

KW - Animals

KW - Animals, Newborn

KW - Attention Deficit Disorder with Hyperactivity

KW - Bicyclo Compounds, Heterocyclic

KW - Discrimination (Psychology)

KW - Disease Models, Animal

KW - Hippocampus

KW - Male

KW - Nicotinic Agonists

KW - Odors

KW - Rats

KW - Rats, Wistar

KW - Set (Psychology)

KW - Tetrodotoxin

KW - Touch

U2 - 10.1038/npp.2012.106

DO - 10.1038/npp.2012.106

M3 - Journal article

C2 - 22781844

SN - 1470-634X

SN - 1740-634X

VL - 37

SP - 2476

EP - 2486

JO - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

IS - 11

ER -