The corticostriatal system in response flexibility and spatial cognition

The corticostriatal system has been suggested to play a role in cognitive functions, but its importance for spatial cognition has been scarcely studied. Different neurological and psychiatric diseases, such as Parkinson’s disease and schizophrenia, are related to (cortico)striatal dysfunctions. These disorders are characterized by motor impairments and psychotic episodes, but cognitive problems occur as well, specifically during early phases of these disorders. These cognitive deficits are largely intractable with available treatment, remain chronically present throughout the course of the disease, and are linked to poor functional prognosis of patients. The most important goal of this dissertation was to investigate the corticostriatal system in relation to spatial-cognitive functions and behavioural flexibility. We reported differential and time-dependent involvement of the dorsomedial (DMS) and dorsolateral (DLS) parts of the striatum in spatial cognition. DMS, but not DLS, was crucial to acquire spatial information and subsequent deployment of spatial search strategies during early learning phases. Furthermore, we revealed decreased DMS involvement as learning progressed or when adjustments in navigation were required. These results suggest a role for DMS during spatial navigation, when contextual information is used to develop and use a spatial search strategy, and when behaviour is still flexible. DMS receives direct input from the anterior cingulate cortex (aCC) and both Arc expression levels and aCC/DMS disruption lesions demonstrated that aCC/DMS connectivity is crucial for spatial cognition. By and large, our experiments identified DMS and aCC/DMS connectivity as central anatomical substrates in response flexibility and spatial learning. These findings relate to cognitive deficits of disorders with corticostriatal (dys)functioning and may show the way for possible treatment of these devastating disorders.status: publishe

Inability to acquire spatial information and deploy spatial search strategies in mice with lesions in dorsomedial striatum

Dorsal striatum has been shown to contribute to spatial learning and memory, but the role of striatal subregions in this important aspect of cognitive functioning remains unclear. Moreover, the spatial-cognitive mechanisms that underlie the involvement of these regions in spatial navigation have scarcely been studied. We therefore compared spatial learning and memory performance in mice with lesions in dorsomedial (DMS) and dorsolateral striatum (DLS) using the hidden-platform version of the Morris water maze (MWM) task. Compared to sham-operated controls, animals with DMS damage were impaired during MWM acquisition training. These mice displayed delayed spatial learning, increased thigmotaxis, and increased search distance to the platform, in the absence of major motor dysfunction, working memory defects or changes in anxiety or exploration. They failed to show a preference for the target quadrant during probe trials, which further indicates that spatial reference memory was impaired in these animals. Search strategy analysis moreover demonstrated that DMS-lesioned mice were unable to deploy cognitively advanced spatial search strategies. Conversely, MWM performance was barely affected in animals with lesions in DLS. In conclusion, our results indicate that DMS and DLS display differential functional involvement in spatial learning and memory. Our results show that DMS, but not DLS, is crucial for the ability of mice to acquire spatial information and their subsequent deployment of spatial search strategies. These data clearly identify DMS as a crucial brain structure for spatial learning and memory, which could explain the occurrence of neurocognitive impairments in brain disorders that affect the dorsal striatum.publisher: Elsevier articletitle: Inability to acquire spatial information and deploy spatial search strategies in mice with lesions in dorsomedial striatum journaltitle: Behavioural Brain Research articlelink: http://dx.doi.org/10.1016/j.bbr.2015.11.001 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

Telencephalic neurocircuitry and synaptic plasticity in rodent spatial learning and memory

Spatial learning and memory in rodents represent close equivalents of human episodic declarative memory, which is especially sensitive to cerebral aging, neurodegeneration, and various neuropsychiatric disorders. Many tests and protocols are available for use in laboratory rodents, but Morris water maze and radial-arm maze remain the most widely used as well as the most valid and reliable spatial tests. Telencephalic neurocircuitry that plays functional roles in spatial learning and memory includes hippocampus, dorsal striatum and medial prefrontal cortex. Prefrontal-hippocampal circuitry comprises the major associative system in the rodent brain, and is critical for navigation in physical space, whereas interconnections between prefrontal cortex and dorsal striatum are probably more important for motivational or goal-directed aspects of spatial learning. Two major forms of synaptic plasticity, namely long-term potentiation, a lasting increase in synaptic strength between simultaneously activated neurons, and long-term depression, a decrease in synaptic strength, have been found to occur in hippocampus, dorsal striatum and medial prefrontal cortex. These and other phenomena of synaptic plasticity are probably crucial for the involvement of telencephalic neurocircuitry in spatial learning and memory. They also seem to play a role in the pathophysiology of two brain pathologies with episodic declarative memory impairments as core symptoms, namely Alzheimer's disease and schizophrenia. Further research emphasis on rodent telencephalic neurocircuitry could be relevant to more valid and reliable preclinical research on these most devastating brain disorders. This article is part of a Special Issue entitled SI: Brain and Memory.publisher: Elsevier articletitle: Telencephalic neurocircuitry and synaptic plasticity in rodent spatial learning and memory journaltitle: Brain Research articlelink: http://dx.doi.org/10.1016/j.brainres.2015.01.015 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

Comparison of the spatial-cognitive functions of dorsomedial striatum and anterior cingulate cortex in mice.

Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a corticostriatal circuit with putative roles in learning and other cognitive functions. In the present study, the spatial-cognitive importance of aCC and DMS was assessed in the hidden-platform version of the Morris water maze (MWM). Brain lesion experiments that focused on areas of connectivity between these regions indicated their involvement in spatial cognition. MWM learning curves were markedly delayed in DMS-lesioned mice in the absence of other major functional impairments, whereas there was a more subtle, but still significant influence of aCC lesions. Lesioned mice displayed impaired abilities to use spatial search strategies, increased thigmotaxic swimming, and decreased searching in the proximity of the escape platform. Additionally, aCC and DMS activity was compared in mice between the early acquisition phase (2 and 3 days of training) and the over-trained high-proficiency phase (after 30 days of training). Neuroplasticity-related expression of the immediate early gene Arc implicated both regions during the goal-directed, early phases of spatial learning. These results suggest the functional involvement of aCC and DMS in processes of spatial cognition that model associative cortex-dependent, human episodic memory abilities

Spatial learning in the Morris water maze test.

<p>Animals with lesions in DMS (n = 9; filled circles, black bar) (A) required significantly more time to locate the hidden platform, (B) spent more time along the walls of the pool, (C) searched further away from the location of the hidden, and (D and E) swam slower from the second day of training compared to sham control group (n = 12; filled squares, grey bar). No overall differences between aCC (n = 11; empty circles, white bar) and sham control group were reported. Represented data are expressed as means ±SEM. * indicates significant differences between the sham control and lesion groups: *<i>p</i> < 0.05, **<i>p</i> < 0.01, ***<i>p</i> < 0.001.</p

NMDA receptor binding is reduced within mesocorticolimbic regions following chronic inhalation of toluene in adolescent rats

The purposeful inhalation of volatile solvents, such as toluene, to induce self-intoxication is prevalent, particularly within adolescent populations. Chronic misuse results in cognitive and neurobiological impairments, as well as an increased risk for addictive behaviours in adulthood. Toluene-induced neuroadaptations within mesocorticolimbic circuitry are thought, in part, to mediate some of the adverse outcomes of toluene misuse, however our understanding of the neuroadaptive processes remains equivocal. An understanding of these processes is particularly important relative to exposure that occurs during adolescence and at concentrations that reflect various patterns of use. Therefore, we exposed male adolescent Wistar rats (postnatal day [PN] 27) to either air or low or high concentrations of inhaled toluene in a chronic and intermittent fashion (CIT, 3,000 or 10,000ppm) for 1 h/day, 3-5 times per week for 4 weeks to model different patterns of human inhalant abuse. Brains were subsequently analysed using autoradiography, qPCR and immunohistochemistry 3 days following the exposure period to investigate toluene-induced neuroadaptations within mesocorticolimbic circuitry. In CIT-exposed rats binding to N-methyl-D-aspartate (NMDA) receptors containing the GluN2B subunit, as determined using [(3)H]-ifenprodil, was decreased in a concentration-related manner in the caudal cingulate cortex, dorsal striatum and accumbens; however, this was not associated with changes in GluN2B protein expression. There were no differences in [(3)H]-epibatidine binding to heteromeric neuronal nicotinic acetylcholine (nACh) receptors. Relative expression of mRNA transcripts encoding NMDA, nACh, γ-aminobutyric acid type-A (GABAA) and dopamine receptor subunits was unchanged in all regions assessed following CIT. Our data suggest that adolescent CIT exposure impacts NMDA receptors within regions of corticostriatal circuitry, possibly via post-translational mechanisms. Dysfunctional glutamatergic signalling within corticostriatal regions may contribute to the adverse outcomes observed following adolescent toluene abuse.status: publishe

Motor performance and working memory.

<p>(A) Average fall latencies over 4 consecutive trials on the accelerated rotarod in aCC- (n = 11; white bar), DMS- (n = 9; black bar) and sham control-lesioned mice (n = 12; grey bar) indicated no motor deficits. (B) Percentage of spontaneous alternations in the y-maze showed no differences in spatial working memory between the groups, and (C) total number of arm entries showed unchanged spontaneous locomotor activity.</p

Search strategies to locate the hidden platform.

<p>Search strategies to locate the hidden platform.</p