Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long–Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication

Effect of General Anesthesia in Infancy on Long-Term Recognition Memory in Humans and Rats

Anesthesia in infancy impairs performance in recognition memory tasks in mammalian animals, but it is unknown if this occurs in humans. Successful recognition can be based on stimulus familiarity or recollection of event details. Several brain structures involved in recollection are affected by anesthesia-induced neurodegeneration in animals. Therefore, we hypothesized that anesthesia in infancy impairs recollection later in life in humans and rats. Twenty eight children ages 6–11 who had undergone a procedure requiring general anesthesia before age 1 were compared with 28 age- and gender-matched children who had not undergone anesthesia. Recollection and familiarity were assessed in an object recognition memory test using receiver operator characteristic analysis. In addition, IQ and Child Behavior Checklist scores were assessed. In parallel, thirty three 7-day-old rats were randomized to receive anesthesia or sham anesthesia. Over 10 months, recollection and familiarity were assessed using an odor recognition test. We found that anesthetized children had significantly lower recollection scores and were impaired at recollecting associative information compared with controls. Familiarity, IQ, and Child Behavior Checklist scores were not different between groups. In rats, anesthetized subjects had significantly lower recollection scores than controls while familiarity was unaffected. Rats that had undergone tissue injury during anesthesia had similar recollection indices as rats that had been anesthetized without tissue injury. These findings suggest that general anesthesia in infancy impairs recollection later in life in humans and rats. In rats, this effect is independent of underlying disease or tissue injury

The Episodic Memory System: Neurocircuitry and Disorders

The ability to encode and retrieve our daily personal experiences, called episodic memory, is supported by the circuitry of the medial temporal lobe (MTL), including the hippocampus, which interacts extensively with a number of specific distributed cortical and subcortical structures. In both animals and humans, evidence from anatomical, neuropsychological, and physiological studies indicates that cortical components of this system have key functions in several aspects of perception and cognition, whereas the MTL structures mediate the organization and persistence of the network of memories whose details are stored in those cortical areas. Structures within the MTL, and particularly the hippocampus, have distinct functions in combining information from multiple cortical streams, supporting our ability to encode and retrieve details of events that compose episodic memories. Conversely, selective damage in the hippocampus, MTL, and other structures of the large-scale memory system, or deterioration of these areas in several diseases and disorders, compromises episodic memory. A growing body of evidence is converging on a functional organization of the cortical, subcortical, and MTL structures that support the fundamental features of episodic memory in humans and animals