The habenular nuclei project through the fasciculus retroflexus (FR) to the midbrain tegmentum, forming an anatomical link between nuclei in the basal forebrain-limbic telencephalon and midbrain nuclei which project back to forebrain. There is evidence that the habenulae exert a tonic inhibitory influence on 1) midbrain dopaminergic systems, and 2) plasma levels of stress- related hormones, catecholamines and glucocorticoids. Lesion of the FR in rats produces behaviors (hyperactivity, stereotypy, deficits in active avoidance and learning tasks) suggestive of an impairment in the ability to respond adaptively to novel or stressful situations, a deficit also characteristic of some types of human psychopathology, including schizophrenia, anxiety and depression. In this study, we will test whether FR lesions increase dopaminergic utilization and/or receptor binding in the striatum, nucleus accumbens (NA) and/or medial prefrontal cortex (mPFC). Based on evidence of functional interactions between adrenocortical and dopaminergic systems, we will also test whether the elevated plasma corticosterone levels of FR-lesioned rats are associated with decreased glucocorticoid receptor (GR)-mediated feedback control by measuring levels of gene expression and immunoreactivity for GRs in ventral tegmental area (VTA), substantia nigra (SN), striatum, NAc and mPFC. We will further explore the functional role of the habenular nuclei in generating a behavioral deficit which can also be experimentally induced by dopaminergic agonists. We hypothesize that FR-lesioned rats demonstrate attentional deficits which may underlie some of the perseverative behaviors which characterize their performance in tests of spontaneous activity and learning tasks. We will test this using a behavioral paradigm assessing latent inhibition of a conditioned emotional response after unpaired preexposure to the conditioned stimulus. FR-lesion-induced locomotor activity and stereotypic behaviors will also be evaluated in all animals. Altered dopaminergic transmission characterizes a number of psychiatric disorders, including schizophrenia, Tourette syndrome and attention deficit hyperactivity disorder. With these studies, we hope to explore the potential utility of the FR-lesioned rat as a model for psychiatric disorders associated with hyperactivity of dopaminergic systems.
