Regional changes in gene expression after limbic kindling.

Repeated electrical stimulation results in development of seizures and a permanent increase in seizure susceptibility (kindling). The permanence of kindling suggests that chronic changes in gene expression are involved. Kindling at different sites produces specific effects on interictal behaviors such as spatial cognition and anxiety, suggesting that causal changes in gene expression might be restricted to the stimulated site. We employed focused microarray analysis to characterize changes in gene expression associated with amygdaloid and hippocampal kindling. Male Long-Evans rats received 1 s trains of electrical stimulation to either the amygdala or hippocampus once daily until five generalized seizures had been kindled. Yoked control rats carried electrodes but were not stimulated. Rats were euthanized 14 days after the last seizures, both amygdala and hippocampus dissected, and transcriptome profiles compared. Of the 1,200 rat brain-associated genes evaluated, 39 genes exhibited statistically significant expression differences between the kindled and non-kindled amygdala and 106 genes exhibited statistically significant differences between the kindled and non-kindled hippocampus. In the amygdala, subsequent ontological analyses using the GOMiner algorithm demonstrated significant enrichment in categories related to cytoskeletal reorganization and cation transport, as well as in gene families related to synaptic transmission and neurogenesis. In the hippocampus, significant enrichment in gene expression within categories related to cytoskeletal reorganization and cation transport was similarly observed. Furthermore, unique to the hippocampus, enrichment in transcription factor activity and GTPase-mediated signal transduction was identified. Overall, these data identify specific and unique neurochemical pathways chronically altered following kindling in the two sites, and provide a platform for defining the molecular basis for the differential behaviors observed in the interictal period.

Using rat ultrasonic vocalization to study the neurobiology of emotion: from basic science to the development of novel therapeutics for affective disorders.

The use of ultrasonic vocalizations as an experimental tool for studying emotional states in rodents has led to an increased understanding of the basic science of affect as well as the development of novel diagnostics and therapeutics for the treatment of affective disorders. At the behavioral level, the rules that govern the generation of affective 'feeling' states are similar to those of the psychophysics of sensory perception. Emotions are elicited primarily in response to active social stimuli. A linear increase in affective response requires a logarithmic increase in stimulation and habituation of a given affective response allows for transition across the cycle of emotional/affective states (approach→consummatory phase→avoidance). At the neuronal level, the coordinated expression of affective responses in the medial prefrontal cortex is orchestrated by rhythmic activity, which is initiated and maintained by a variety of short-term and long-term synaptic plasticity processes. An objective measure of affective states may emerge from these psychophysical and neuronal properties of emotion. Enhancing synaptic plasticity with pharmacological agents that modulate NMDA receptor activity as well as IGFI receptor activity may have therapeutic potential for the treatment of affective disorders.