Kjesten A. Wiig

Corticohippocampal Contributions to Spatial and Contextual Learning

Spatial and contextual learning are considered to be dependent on the hippocampus, but the extent to which other structures in the medial temporal lobe memory system support these functions is not well understood. This study examined the effects of individual and combined lesions of the perirhinal, postrhinal, and entorhinal cortices on spatial and contextual learning. Lesioned subjects were consistently impaired on measures of contextual fear learning and consistently unimpaired on spatial learning in the Morris water maze. Neurotoxic lesions of perirhinal or postrhinal cortex that were previously shown to impair contextual fear conditioning (Bucci et al., 2000) or contextual discrimination (Bucci et al., 2002) caused little or no impairment in place learning and incidental learning in the water maze. Combined lesions of perirhinal plus lateral entorhinal or postrhinal plus medial entorhinal cortices resulted in deficits in acquisition of contextual discrimination but had no effect on place learning in the water maze. Finally, a parahippocampal lesion comprising combined neurotoxic damage to perirhinal, postrhinal, and entorhinal cortices resulted in profound impairment in acquisition of a standard passive avoidance task but failed to impair place learning. In the same experiment, rats with hippocampal lesions were impaired in spatial navigation. These results indicate that tasks requiring the association between context and an aversive stimulus depend on corticohippocampal circuitry, whereas place learning in the water maze can be accomplished without the full complement of highly processed information from the cortical regions surrounding the hippocampus. The evidence that different brain systems underlie spatial navigation and contextual learning has implications for research on memory when parahippocampal regions are involved.

A molecular correlate of memory and amnesia in the hippocampus

Memory consolidation in humans and other species is profoundly disrupted by lesions of either the medial temporal lobes or regions of the thalamus. It has been proposed that these structures regulate the neuronal gene expression necessary for long-term memory. Evidence suggests that long-term memory formation requires the activity of members of the cAMP response element (CRE) binding protein (CREB) transcription factor family, and that CRE-regulated genes are expressed in the hippocampus in response to inhibitory avoidance training. Here we show that lesions of the fornix, a massive fiber bundle connecting the hippocampus with the septum and hypothalamus, specifically disrupt both consolidation of inhibitory avoidance memory and CREB-mediated responses in the hippocampus. We propose that inputs passing through the fornix regulate this memory consolidation by regulating CREB-mediated gene expression in hippocampal neurons.

Memory impairment on a delayed non-matching-to-position task after lesions of the perirhinal cortex in the rat

Previous research conducted in monkeys and rats has established that the perirhinal cortex is critically involved in object- or stimulus-recognition memory, whereas other research suggests this region may contribute to memory for object discriminations. These findings do not rule out the possibility that the perirhinal cortex plays a more general role in memory. The present experiment addressed whether selective lesions of the perirhinal cortex would result in a delay-dependent deficit on a test of memory that did not involve stimulus recognition or object memory. Rats with bilateral perirhinal lesions were tested on a delayed non-matching-to-position task. Lesions of the perirhinal cortex did not interfere with acquisition or performance at short (0-4 s)-delay intervals, but lesions did impair performance at longer delays. It is suggested that the perirhinal cortex is involved in maintaining representations of trial-specific information over time.

The levo enantiomer of amphetamine increases memory consolidation and gene expression in the hippocampus without producing locomotor stimulation.

Dextro-amphetamine enhances memory and other cognitive functions in animals and humans. The use of d-amphetamine as a memory enhancer, however, is limited by a robust stimulatory side-effect profile caused by release of dopamine. The levo enantiomer of amphetamine has been shown to be considerably less effective as a dopamine releaser and less potent in producing the stimulatory effects characteristic of d-amphetamine. In order to determine whether l-amphetamine and the structurally related compound, l-methamphetamine, retain cognitive-enhancing effects despite their lack of stimulatory activity, we administered the compounds to rats prior to activity monitoring experiments, and in different animals, immediately after training on inhibitory avoidance and object recognition tasks. Results demonstrated that l-amphetamine and l-methamphetamine did not increase locomotion and stereotypies beyond control levels, but did produce significant memory enhancement. In addition, l-amphetamine and l-methamphetamine alleviated scopolamine-induced amnesia in the inhibitory avoidance task. In all cases, these compounds produced an effect comparable to that of d-amphetamine, but required only one quarter of the d-amphetamine dose to produce the same effect size. We also found that l-amphetamine modulates learning-induced changes in hippocampal Arc/Arg3.1 protein synthesis that correlate with memory consolidation. These results suggest that l-amphetamine and l-methamphetamine are potent memory enhancers in rats and may ultimately be useful for treating memory disorders in humans.

Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex

Working memory is an essential component of higher cognitive function, and its impairment is a core symptom of multiple CNS disorders, including schizophrenia. Neuronal mechanisms supporting working memory under normal conditions have been described and include persistent, high-frequency activity of prefrontal cortical neurons. However, little is known about the molecular and cellular basis of working memory dysfunction in the context of neuropsychiatric disorders. To elucidate synaptic and neuronal mechanisms of working memory dysfunction, we have performed a comprehensive analysis of a mouse model of schizophrenia, the forebrain-specific calcineurin knock-out mouse. Biochemical analyses of cortical tissue from these mice revealed a pronounced hyperphosphorylation of synaptic vesicle cycling proteins known to be necessary for high-frequency synaptic transmission. Examination of the synaptic vesicle cycle in calcineurin-deficient neurons demonstrated an impairment of vesicle release enhancement during periods of intense stimulation. Moreover, brain slice and in vivo electrophysiological analyses showed that loss of calcineurin leads to a gene dose-dependent disruption of high-frequency synaptic transmission and network activity in the PFC, correlating with selective working memory impairment. Finally, we showed that levels of dynamin I, a key presynaptic protein and calcineurin substrate, are significantly reduced in prefrontal cortical samples from schizophrenia patients, extending the disease relevance of our findings. Our data provide support for a model in which impaired synaptic vesicle cycling represents a critical node for disease pathologies underlying the cognitive deficits in schizophrenia.