Bennet Givens

Galanin in the medial septal area impairs working memory

Galanin, a peptide of 29 amino acids, is co-localized with acetylcholine in a subpopulation of neurons of the medial septal area (MSA) that project to the hippocampus. Galanin reverses the actions of acetylcholine in several biochemical and behavioral procedures, and may be involved in memory processes. To test the possibility that galanin acts on the cell bodies of MSA neurons, two measures of septohippocampal function were assessed following intra-septal microinfusion of galanin or two synthetic fragments of galanin (1-16 and 21-29). The behavioral measure was choice accuracy in a working memory task in a T-maze. The electrophysiological measure was hippocampal theta activity recorded from the dentate hilus. The galanin fragment, 1-16, and the complete peptide, 1-29, decreased choice accuracy and decreased hippocampal theta activity in a dose-dependent fashion. Saline and the 21-29 fragment had no effect on choice accuracy and hippocampal theta. Sensorimotor performance was unaffected. These findings demonstrate that galanin impairs working memory when administered directly into the MSA and suggest that galanin inhibits MSA neural activity.

Ethanol suppresses the induction of long-term potentiation in vivo

Long-term potentiation (LTP), a leading neural mechanism of memory, is profoundly affected by ethanol in vitro, but ethanols effect on LTP in vivo has not been studied at doses known to impair memory. In this study, LTP was induced in the dentate hilus by theta-pattern stimulation of the perforant path. Dentate evoked responses were recorded during a 3 h session in which rats pressed a lever on a fixed interval (30 s) schedule of reinforcement. Following theta-pattern stimulation, rats pretreated with saline had significant LTP that was present throughout the session. LTP was measured as an increase in the initial slope and the population spike of the evoked response. The potentiation was no longer present 24 h after stimulation. Ethanol (0.5 g/kg and 1.0 g/kg) blocked LTP and attenuated short-term frequency potentiation in a dose-dependent fashion. Although ethanol produced a decrease in rewarded lever pressing, lever pressing was not correlated to any measure of the evoked response. Ethanol, when given 60 min after theta-pattern stimulation, did not alter the expression of LTP. The results demonstrate that low doses of ethanol selectively blocked the induction of LTP in vivo, an effect that may underlie ethanols impairment of memory.

Neuronal mechanisms mediating drug-induced cognition enhancement : cognitive activity as a necessary intervening variable

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simultaneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.

Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction in mice.

Several studies suggest that prenatal stress is a possible risk factor in the development of autism spectrum disorders. However, many children exposed to stress prenatally are born healthy and develop typically, suggesting that other factors must contribute to autism. Genes that contribute to stress reactivity may, therefore, exacerbate prenatal stress‐mediated behavioral changes in the adult offspring. One candidate gene linked to increased stress reactivity encodes the serotonin transporter. Specifically, an insertion/deletion (long/short allele) polymorphism upstream of the serotonin transporter gene correlates with differential expression and function of the serotonin transporter and a heightened response to stressors. Heterozygous serotonin transporter knockout mice show reductions in serotonin transporter expression similar to the human short polymorphism. In this study, the role of prenatal stress and maternal serotonin transporter genotype were assessed in mice to determine whether their combined effect produces reductions in social behavior in the adult offspring. Pregnant serotonin transporter heterozygous knockout and wild‐type dams were placed in either a control condition or subjected to chronic variable stress. The adult offspring were subsequently assessed for social interaction and anxiety using a three‐chamber social approach task, ultrasonic vocalization detection, elevated‐plus maze and an open field task. Results indicated that prenatal stress and reduced serotonin transporter expression of the dam may have the combined effect of producing changes in social interaction and social interest in the offspring consistent with those observed in autism spectrum disorder. This data indicates a possible combined effect of maternal serotonin transporter genotype and prenatal stress contributing to the production of autistic‐like behaviors in offspring.

Effect of ethanol on sustained attention in rats.

Abstract Acute exposure to ethanol produces deficits in sustained attention in humans, but these attentional deficits have not been modeled in animals. In this study, an operant task was used to investigate the effects of low and moderate doses of ethanol on sustained attention in rats. Performance on a two-choice reaction time task over a 1-h session was assessed immediately following administration of ethanol (0.0, 0.5, 0.75, 1.0 and 1.5 g/kg IP). Each rat was required to respond to a light stimulus of variable duration (20, 100, and 500 ms) occurring at one of two locations. Under control and saline conditions, increases in stimulus length systematically increased choice accuracy and decreased reaction time. Ethanol produced a dose-dependent decrease in choice accuracy that interacted with time, with an initial impairment that was stimulus length-dependent followed by a general vigilance decrement. The data demonstrate that ethanol impaired the ability of rats to direct and sustain attention to brief, infrequent stimuli, and provide a model for further investigations into the underlying neurobiological mechanisms for ethanol-induced attentional deficits.

Behavioral correlates of single units in the medial septal area: The effect of ethanol

Experimental manipulations that compromise the medial septal area consistently and selectively impair working memory. The electrophysiological and pharmacological properties of medial septal neurons have been studied extensively, but the relation between medial septal neuronal activity and ongoing behavior has not been systematically analysed. Working memory was assessed in a continuous conditional discrimination task, and behavioral performance was correlated with medial septal single unit activity. Operant performance and the activity of rhythmically active neurons were continuously monitored during a 90 min test session, and peri-event time histograms of unit activity were constructed around relevant task events. Rats received intraperitoneal injections of either saline or ethanol (0.75 g/kg) 5 min before testing. Of the 52 medial septal neurons recorded under saline conditions, approximately 80% had significant behavioral correlates. Thirty-five per cent of these neurons were selectively activated at the time of the response and 65% at the time of the reward. Response-related activity was not selective for responses to the right or left lever, or to a particular type of trial, but in 61% of the cases was correlated with the accuracy of the response. In ethanol-treated rats, working memory was impaired, single unit activity was disrupted, and the behavioral correlates were less frequent and robust, especially the response-related correlates that were accuracy-sensitive. The results suggest that the medial septal area is involved in guiding accurate responses and processing rewards, and may contribute to the ethanol-induced impairments in working memory.

Topography of basal glucose utilization in the hippocampus determined with [1-14C]glucose and [6-14C]glucose

The activity of the pentose phosphate shunt was assessed under basal conditions in subregions of the hippocampus by measuring the uptake and retention of [1-14C]glucose and [6-14C]glucose and their 14C-labelled metabolites. The relative and absolute retention of carbon-14 from each of the two compounds was nearly identical in all regions examined. For each compound, the highest accumulation of 14C occurred in the granule cell layer of the dentate gyrus and in the pyramidal cell layer. Relatively high retention of radioactivity was also found in the molecular layer of dentate gyrus and in the stratum lacunosum-molecular. The stratum radiatum and stratum oriens contained the lowest levels of radioactivity among hippocampal regions. The equal retention of radioactivity from [1-14C]glucose and [6-14C]glucose implies that pentose phosphate shunt activity is very low throughout the hippocampus under the conditions of this study. The uptake and retention of radioactivity was evaluated in different hippocampal regions 10 or 30 min following intravenous injection of [1-14C]glucose. Although there was significantly more radioactivity at 30 min than at 10 min, the same topographic pattern of radioactivity within the hippocampus was observed in rats after both survival periods, indicating that an equal fraction of the [1-14C]glucose utilized in different hippocampal regions is oxidized to 14CO2 under these conditions. Most regions of high glucose utilization in the hippocampus determined with [1-14C]glucose and [6-14C]glucose correspond to regions of intense histochemical staining for cytochrome oxidase reported in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)

Low frequency oscillations in rat posterior parietal cortex are differentially activated by cues and distractors

The posterior parietal cortex (PPC) is hypothesized to detect visual cues among competing distractors. Anatomical and neurophysiologic evidence indicates that the rat PPC is part of a network of brain areas involved in directed attention, specifically when new task parameters or conditions are introduced. Here, we test the hypothesis that changes in the local field potential (LFP) of the PPC of rats performing a sustained attention task reflect aspects of detection. Two event-related potentials were observed during detection: the P300 response and the contingent negative variation (CNV). Spectrogram analysis also indicated a detection-specific increase in alpha power in the retention interval of this task. This is consistent with observations from human studies, which indicate that tasks requiring a subject to withhold a response produced a pronounced synchronization of alpha rhythms during the delay, and desynchronization during retrieval. We also found cycles of alpha synchrony and desynchrony in response to a periodic distractor. These cycles were most pronounced in the initial trial block of the distractor when the false alarm rate was highest, and as task performance improved these cycles significantly diminished. This result suggests that alpha cycling in the PPC represent neural activity critical for learning to inhibit distractors. The occurrence of alpha synchronization and desynchronization to attention-demanding stimuli, in addition to the P300 and CNV responses observed during detection, is evidence that rat PPC is involved in sustained attention, particularly in the presence of distractors.

EFFECTS OF PREDATOR-INDUCED STRESS AND AGE ON WORKING MEMORY IN RATS

The effects of age and predator-induced stress, by exposing rats to a cat, were examined during subsequent testing of spatial working memory. Male rats (3 months and 20 months of age) were trained on a spatial delayed-alternation task using an elevated T maze. After subgroups were given intermittent protected-exposure sessions over a 3-day period to cats or to a control condition, they were tested on the working memory task. The old rats took more trials to reach training criterion. Overall, both stress-exposed groups exhibited a decline in accuracy 24 hr later and recovered completely during the subsequent test sessions. Surprisingly, young stressed rats showed significantly greater decrements in accuracy than old stressed rats. However, exposure to the stressor resulted in decreases in response speed that were comparable for both age groups. These findings are discussed in terms of possible changes in glucocorticoids, plasma corticosterone, and endogenous opioids that are known to be affected by age and stress and have been shown to influence spatial working memory.

Working Memory and Cholinergic Autoregulation in the Medial Septal Area

This chapter explores the hypothesis that cholinergic neurotransmission onto GABAergic and cholinergic neurons in the medial septal area (MSA) can elicit rhythmic neural output that coordinates hippocampal information processes and enhances working memory. The MSA is comprised of the medial septal nucleus and the vertical limb of the diagonal band. One of the major efferent projections from the MSA is to the hippocampal, entorhinal, and subicular regions of the temporal lobe. The septohippocampal pathway contains fibers from both cholinergic and GABAergic neurons of the MSA that receive afferent input from GABAergic neurons of the lateral septum, and from cholinergic neurons in the basal forebrain and the brainstem. The GABAergic input to MSA has been well studied anatomically (Leranth and Frotscher, 1989), biochemically (Costa et al., 1983), electrophysiologically (McLennan and Miller, 1974), and behaviorally (Decker and McGaugh, 1991). However, the role of the cholinergic input to MSA neurons is less well characterized and will be the focus of this chapter.