Transient inactivation of the neonatal ventral hippocampus impairs attentional set-shifting behavior: reversal with an α7 nicotinic agonist
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Transient inactivation of the neonatal ventral hippocampus impairs attentional set-shifting behavior : reversal with an α7 nicotinic agonist. / Brooks, Julie M; Pershing, Michelle L; Thomsen, Morten Skøtt; Mikkelsen, Jens D; Sarter, Martin; Bruno, John P.
In: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Vol. 37, No. 11, 10.2012, p. 2476-86.Research output: Contribution to journal › Journal article › Research
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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
VL - 37
SP - 2476
EP - 2486
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 11
ER -
ID: 111179415