Selective effects of perinatal ethanol exposure in medial prefrontal cortex and nucleus accumbens.

Ethanol exposure during development is the leading known cause of mental retardation and can result in characteristic physiological and cognitive deficits, often termed Fetal Alcohol Spectrum Disorders (FASD). Previous behavioral findings using rat models of FASD have suggested that there are changes in the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC) following ethanol exposure during development. This study used a rat model of FASD to evaluate dendritic morphology in both the NAC and mPFC and cell number in the NAC. Dendritic morphology in mPFC and NAC was assessed using a modified Golgi stain and analyzed via three dimensional reconstructions with Neurolucida (MBF Bioscience). Cell counts in the NAC (shell and core) were determined using an unbiased stereology procedure (Stereo Investigator (MBF Bioscience)). Perinatal ethanol exposure did not affect neuronal or glial cell population numbers in the NAC. Ethanol exposure produced a sexually dimorphic effect on dendritic branching at one point along the NAC dendrites but was without effect on all other measures of dendritic morphology in the NAC. In contrast, spine density was reduced and distribution was significantly altered in layer II/III neurons of the mPFC following ethanol exposure. Ethanol exposure during development was also associated with an increase in soma size in the mPFC. These findings suggest that previously observed sexually dimorphic changes in activation of the NAC in a rat model of FASD may be due to altered input from the mPFC.

Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring.

Prenatal stress alters neuronal morphology of mesocorticolimbic structures such as frontal cortex and hippocampus in the adult offspring. We investigated here the effects of prenatal stress on the spine density and the dendrite morphology of hippocampal pyramidal neurons and medium spiny cells from nucleus accumbens in prepubertal and adult male offsprings. Sprague-Dawley pregnant dams were stressed by restraining movement daily for 2 hours from gestational day 11 until delivery. Control mothers remained free in their home cage without water and food during the stressful event. Male offsprings from immobilized and control rats were left to grow until postnatal day (PD) 35 for the prepubertal group, and until PD 65 for the adult group. Spontaneous locomotor activity was assessed and then brains were removed to study the dendritic morphology by the Golgi-Cox stain method followed by Sholl analysis. Prenatally stressed animals demonstrated increased locomotion and alterations in spine density in the hippocampus and nucleus accumbens at both ages. However, prepubertal males showed an increase in spine density in the CA1 hippocampus with a decrease in CA3 hippocampus, whereas the adult group showed a decrease in the spine density in both of the regions studied. These results suggest that prenatal stress carried out during the middle of pregnancy affect the spine density and basal dendrites of pyramidal neurons of hippocampus, as well as the dendritic morphology of nucleus accumbens which may reflect important changes in the mesocorticolimbic dopaminergic transmission and behaviors associated with the development of psychiatric diseases such as schizophrenia.

Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug.

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.

Validity of large-deformation high dimensional brain mapping of the basal ganglia in adults with Tourette syndrome.

The basal ganglia and thalamus may play a critical role for behavioral inhibition mediated by prefrontal, parietal, temporal, and cingulate cortices. The cortico-basal ganglia-thalamo-cortical loop with projections from frontal cortex to striatum, then to globus pallidus or to substantia nigra pars reticulata, to thalamus and back to cortex, provides the anatomical substrate for this function. In-vivo neuroimaging studies have reported reduced volumes in the thalamus and basal ganglia in individuals with Tourette Syndrome (TS) when compared with healthy controls. However, patterns of neuroanatomical shape that may be associated with these volume differences have not yet been consistently characterized. Tools are being developed at a rapid pace within the emerging field of computational anatomy that allow for the precise analysis of neuroanatomical shape derived from magnetic resonance (MR) images, and give us the ability to characterize subtle abnormalities of brain structures that were previously undetectable. In this study, T1-weighted MR scans were collected in 15 neuroleptic-naïve adults with TS or chronic motor tics and 15 healthy, tic-free adult subjects matched for age, gender and handedness. We demonstrated the validity and reliability of large-deformation high dimensional brain mapping (HDBM-LD) as a tool to characterize the basal ganglia (caudate, globus pallidus and putamen) and thalamus. We found no significant volume or shape differences in any of the structures in this small sample of subjects.

Thought disorder and nucleus accumbens in childhood: a structural MRI study.

Thought disorder has been described as a hallmark feature in both adult and childhood-onset schizophrenia. The nucleus accumbens (NAc) has been repeatedly proposed as a critical station for modulating gating of information flow and processing of information within the thalamocortical circuitry. The aim of the present study was to investigate the relationship of thought disorder measures, which were administered to 12 children with schizophrenia and 15 healthy age-matched controls, and NAc volumes obtained from high-resolution volumetric magnetic resonance imaging analyses. The propensity for specific thought disorder features was significantly related to NAc volumes, despite no statistically significant differences in the NAc volumes of children with schizophrenia and normal children. Smaller left NAc volumes were significantly related to poor on-line revision of linguistic errors in word choice, syntax and reference. On the other hand, underuse of on-line repair of errors in planning and organizing thinking was significantly associated with decreased right NAc volumes. The results of this pilot study suggest that the NAc is implicated in specific thought patterns of childhood. They also suggest that subcortical function in the NAc might reflect hemispheric specialization patterns with left lateralization for revision of linguistic errors and right lateralization for repair strategies involved in the organization of thinking.

Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory.

Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.

Novel cerebral lesions in the Eker rat model of tuberous sclerosis: cortical tuber and anaplastic ganglioglioma.

The Eker rat is a model for human tuberous sclerosis (TSC) caused by a mutation in the Tsc2 gene. We describe here histological and immunohistochemical findings of the brain lesions in Eker rats, with emphasis on 2 novel lesions found in this study: a cortical tuber and an anaplastic ganglioglioma. The rat cortical tuber resembled those of humans, and further confirmed the value of this animal model as a tool for investigating the molecular pathology of tuberous sclerosis. On the other hand, the rat anaplastic ganglioglioma had features of a malignant neoplasm that are absent from human subependymal giant cell astrocytomas.