Neuronal correlates of signal detection in the posterior parietal cortex of rats performing a sustained attention task.

The posterior parietal cortex (PPC) plays an integral role in visuospatial attention. Evidence suggests that neuronal activity in the PPC predicts the allocation of attention to stimuli. The present experiment tested the hypothesis that in rats performing a sustained attention task, the detection of signals, as opposed to missed signals, is associated with increased PPC unit activity. Single unit activity was recorded from the PPC of rats and analyzed individually and as a population vector for each recording session. A population of single units (28/111) showed significant activation evoked by signals on trials resulting in correct performance (hits). A smaller population of neurons (three/111) was activated on trials in which signals were not detected by the animals (misses). Analysis of populations of simultaneously recorded neurons indicated increased activation predicting signal detection; no population of neurons was activated on trials in which the animal incorrectly pressed the hit lever following nonsignals. The increased, hit-predicting activity was not modulated by signal duration or the presence of a visual distractor, although the distractor reduced the number of trials in which hit-predicting activity and subsequent correct detection occurred. These findings indicate that attentional signal processing in the PPC integrates successful detection of signals.

Stimulation-induced reset of hippocampal theta in the freely performing rat.

Previous research has suggested that visual and auditory stimuli in a working memory task have the ability to reset hippocampal theta, perhaps allowing an organism to encode the incoming information optimally. The present study examined two possible neural pathways involved in theta resetting. Rats were trained on a visual discrimination task in an operant chamber. At the beginning of a trial, a light appeared over a centrally located lever that the rat was required to press to receive a water reward. There was a 30-s intertrial interval before the next light stimulus appeared. After learning the task, all rats received surgical implantation of stimulating electrodes in both the fornix and the perforant path and recording electrodes, bilaterally in the hippocampus. After surgery, theta was recorded before and after the light stimulus to determine whether resetting to the visual stimulus occurred. During the intertrial interval, rats received single-pulse electrical stimulation of either the fornix or perforant path. Theta was recorded both before and after the electrical stimulation to determine whether resetting occurred. In this experiment, hippocampal theta was reset after all three stimulus conditions (light, perforant path, and fornix stimulation), with the greatest degree of reset occurring after the fornix stimulation. The results suggest that activation of the perforant path and fornix may underlie theta reset and provide a mechanism by which the hippocampus may enhance cognitive processing.

The cognitive neuroscience of sustained attention: where top-down meets bottom-up.

The psychological construct 'sustained attention' describes a fundamental component of attention characterized by the subject's readiness to detect rarely and unpredictably occurring signals over prolonged periods of time. Human imaging studies have demonstrated that activation of frontal and parietal cortical areas, mostly in the right hemisphere, are associated with sustained attention performance. Animal neuroscientific research has focused on cortical afferent systems, particularly on the cholinergic inputs originating in the basal forebrain, as crucial components of the neuronal network mediating sustained attentional performance. Sustained attention performance-associated activation of the basal forebrain corticopetal cholinergic system is conceptualized as a component of the 'top-down' processes initiated by activation of the 'anterior attention system' and designed to mediate knowledge-driven detection and selection of target stimuli. Activated cortical cholinergic inputs facilitate these processes, particularly under taxing attentional conditions, by enhancing cortical sensory and sensory-associational information processing, including the filtering of noise and distractors. Collectively, the findings from human and animal studies provide the basis for a relatively precise description of the neuronal circuits mediating sustained attention, and the dissociation between these circuits and those mediating the 'arousal' components of attention.

Sustained visual attention performance-associated prefrontal neuronal activity: evidence for cholinergic modulation.

Cortical cholinergic inputs are hypothesized to mediate attentional functions. The present experiment was designed to determine the single unit activity of neurons within the medial prefrontal cortex (mPFC) of rats performing a sustained visual attention task. Demands on attentional performance were varied by the presentation of a visual distractor. The contribution of cholinergic afferents of the mPFC to performance-associated unit activity within this area was determined by recording neuronal activity before and after unilateral cholinergic deafferentation using intracortical infusion of the immunotoxin 192 IgG-saporin. Presentation of the visual distractor resulted in a decrease in the detection of brief, unpredictable visual signals. As predicted, the unilateral loss of cholinergic inputs within the recording area of the mPFC did not affect sustained attentional performance. Cholinergic deafferentation, however, resulted in a decrease in the overall firing rate of medial prefrontal neurons and a substantial reduction in the proportion of neurons whose firing patterns correlated with specific aspects of behavioral performance. Furthermore, cholinergic deafferentation attenuated the frequency and amplitude of increased mPFC neuronal firing rates that were associated with the presentation of the visual distractor. The main findings from this experiment suggest that cholinergic inputs to the mPFC strongly influence spontaneous and behaviorally correlated single unit activity and mediate increases in neuronal activity associated with enhanced demands for attentional processing, all of which may be fundamental aspects in the maintenance of attentional performance.

Septohippocampal pathway as a site for the memory-impairing effects of ethanol.

Ethanol affects behavior by interacting with synaptic sites at many levels of the nervous system. However, it targets most readily and at the lowest concentrations those sites mediating higher cognitive functions such as attention and memory. The memory-impairing effects of ethanol are thought to involve the hippocampus, a structure particularly vulnerable to the effects ethanol at low concentrations and early in the rising phase of the blood ethanol concentration curve. One of the early, low-dose effects of ethanol is an interruption of the normal physiological regulation of the hippocampus by the ascending septohippocampal pathway originating in the medial septal area (MSA). Ethanol enhances GABAergic transmission in the MSA, thereby reducing the regularity and vigor with which rhythmically bursting neurons of the MSA drive the hippocampal theta rhythm. Disruption of septohippocampal activity also has consequences on the response of the hippocampus to cortical inputs. Ethanol produces a loss of hippocampal responsivity that reduces the ability of the hippocampus to encode and retrieve relevant stimulus information necessary for accurate memory. This paper examines the behavioral and neural evidence for hippocampal vulnerability to ethanol and explores the hypothesis that these effects are due to ethanol disrupting septohippocampal modulation of the hippocampus, resulting in impairments of memory.

Cognitive correlates of single neuron activity in task-performing animals: application to ethanol research.

The deleterious effects of ethanol on cognitive processes result from an interaction between ethanol and the neural structures that are critical for executing those cognitive functions. Results from studies that employ contemporary behavioral neuroscience techniques are beginning to elucidate the neural circuits that underlie specific cognitive processes, and the stage is set for rigorous investigations into the neural basis for ethanol-induced cognitive impairments. In this article, the application of single neuron recording techniques to the study of the memory and attentional deficits produced by acute exposure to low levels of ethanol are described, with an emphasis on the advantages of combining physiological techniques with operant behavioral procedures in rats. After reviewing background information on the basic neurophysiological and behavioral techniques, empirical results from this laboratory will be used to illustrate how single-unit analysis can be applied to the study of ethanol-induced cognitive impairments.

MMR2 immunization at 4 to 5 years and 10 to 12 years of age: a comparison of adverse clinical events after immunization in the Vaccine Safety Datalink project. The Vaccine Safety Datalink Team.

BACKGROUND: The Advisory Committee on Immunization Practices recommends a second dose of measles, mumps, and rubella vaccine (MMR2) at age 4 to 5 years of age, whereas the American Academy of Pediatrics suggests MMR2 immunization at age 11 to 12 years of age. Because there is little information on whether the rate of adverse reactions to MMR2 immunization varies among these two age groups, we took advantage of differing immunization policies at two large HMOs to compare the frequency of clinical events after, and possibly related to, MMR2 immunization. METHODS: Information was collected on clinical events plausibly associated to MMR immunization (seizures, pyrexia, malaise/fatigue, nervous/musculoskeletal symptoms, rash, edema, induration/ecchymoses, lymphadenopathy, thrombocytopenia, aseptic meningitis, and joint pain) in two cohorts. At three facilities at Northern California Kaiser (Oakland, CA), 8514 children received MMR2 immunization at age 4 to 6 years of age; at Group Health Cooperative (Seattle, WA) 18 036 children received MMR2 immunization at age 10 to 12 years of age. To account for age-related differences in health care use, within each HMO, clinical events in a 30-day period after immunization were compared with a 30-day period before vaccination. RESULTS: Children 10 to 12 years of age were 50% more likely to have a clinical event after MMR2 immunization than in the period before immunization (odds ratio, 1.45; 95% confidence interval: 1.00,2.10). Children 4 to 6 years of age were less likely to have a visit for an event after immunization compared with the period before immunization (odds ratio, 0.64; 95% confidence interval: 0.40,1.01). CONCLUSIONS: These results suggest that the risk for clinical events after MMR2 immunizations is greater in the 10- to 12-year age group.

Effects of ethanol on nonspatial working memory and attention in rats.

Investigation into the neural basis for ethanol-induced cognitive dysfunction requires the use of valid animal models. An operant signal detection procedure was developed to assess simultaneously the processes of sustained attention and working memory in rats, and to determine the effects of ethanol on these cognitive functions. Ethanol, at 0.75 g/kg ip, produced delay- and stimulus length-dependent decreases in choice accuracy, effects that are consistent with deficits in both working memory and sustained attention. Local infusion of ethanol directly into the medial septal area resulted in a selective loss of choice accuracy at the long delay. The impairment by intraseptal ethanol did not interact with stimulus length. Thus, the working memory impairment, but not the decrement in sustained attention, was mimicked by intraseptal ethanol. The current model provides a foundation for studying the neural basis of ethanol's cognitive effects.

Modulation of cognitive processes by transsynaptic activation of the basal forebrain.

Each of the neurotransmitter-specific afferents to the basal forebrain (BF) carry different types of information which converge to regulate the activity of cholinergic projections to telencephalic areas. Brainstem monoaminergic and cholinergic inputs are critical for context-dependent arousal. GABAergic afferents are gated by a variety of ascending and descending systems, and in addition provide an intrinsic control of BF output excitability. Corticofugal glutamatergic inputs represent reciprocal connections from sites to which BF afferents project, and carry information about the current level of cortical processing intensity and capacity. Peptidergic inputs arise from hypothalamic sources and locally modulate BF output as a function of motivational and homeostatic processes. The significance of these afferent systems can be studied by examining the behavioral consequences of infusion into the BF of drugs that act on the specific receptor systems. Although traditional analyses suggest that the BF has many behavioral functions that can be subdivided regionally, an analysis of studies employing transsynaptic approaches lead to the conceptualization of the BF as having a uniform function, that of maximizing cortical processing efficiency. The BF is conditionally active during specific episodes of acquisition and processing of behaviorally significant, externally-derived information, and drives cortical targets into a state of readiness by reducing interference and amplifying the processing of relevant stimuli and associations, thus allowing for more efficient processing. This paper describes the transsynaptic approach to studying BF function, reviews the neurobiological and behavioral consequences of altering neurotransmitter-specific inputs to the BF, and explores the functional significance of the BF.

Effect of ethanol on sustained attention in rats.

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 i.p.). 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 systemically 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.

Stimulus-evoked resetting of the dentate theta rhythm: relation to working memory.

The relationship between memory and rhythmic neural activity in the dentate gyrus was investigated by analyzing spontaneous dentate field potentials in rats performing either a working or reference memory task. The baseline level of rhythmic theta activity was similar in both groups. Following an initial negative potential in the sensory-evoked response, a resetting of the rhythmic activity which was time-locked to the stimulus onset was observed in rats performing the working memory task, but not in rats performing the reference memory task. The results suggest that the resetting of the theta rhythm by behaviorally-relevant stimuli may have an important role in working 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.

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.

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 ethanol's 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 ethanol's impairment of memory.

Low doses of ethanol impair spatial working memory and reduce hippocampal theta activity.

Low doses of ethanol can alter neural activity in the septohippocampal pathway, a pathway critical for spatial working memory. The present study was designed to determine whether acute ethanol induces impairments in working memory and disrupts septohippocampal function as measured by the hippocampal theta rhythm. Rats were preoperatively trained on delayed alternation. A within-subject design was used to evaluate the effects of ethanol (0.25, 0.5, 0.75 and 1.0 g/kg, intraperitoneally) on performance 10 min and 90 min after injection as compared with preinjection baseline. Ethanol produced dose-, delay-, and time-dependent impairments in working memory as indicated by a change in choice accuracy in the delayed alternation task. Ethanol did not affect performance time, the ability to complete the task, or response bias. Thus, the impairment does not appear to result from a decrement in general performance, but rather from an impairment in spatial working memory. Hippocampal theta activity was suppressed by ethanol at the same doses, 0.75 g/kg and 1.0 g/kg, that impaired working memory. The interaction of ethanol with functions of the septohippocampal pathway are discussed.

Bidirectional modulation of scopolamine-induced working memory impairments by muscarinic activation of the medial septal area.

The hypotheses that the medial septal area (MSA) is critical for working memory and that MSA neural activity is positively regulated by cholinergic inputs leads to two testable predictions: (1) working memory can be bidirectionally modulated by muscarinic manipulations of the MSA and (2) muscarinic activation of the MSA can enhance memory under conditions of mnemonic impairment. Memory was assessed by T-maze spatial alternation following intraseptal infusion of muscarinic drugs in rats pretreated with intraperitoneal (IP-) injections of scopolamine. Scopolamine dose-dependently impaired working memory and shifted the hippocampal theta activity to a higher peak frequency. Intraseptal scopolamine mimicked the behavioral effects of IP-scopolamine, and intraseptal carbachol appeared to reverse both the behavioral and physiological effects of IP-scopolamine. The results indicate that the amnestic effect of antimuscarinic drugs may be due to an interaction in the MSA and that conditions of memory impairment may be alleviated by selective muscarinic activation of the MSA.

Cholinergic manipulations in the medial septal area: age-related effects on working memory and hippocampal electrophysiology.

Aged rats have impairments in several types of cognitive functions, including spatial working memory (WM), that are dependent upon the septohippocampal cholinergic system. The present series of experiments was designed to assess the effectiveness of pharmacological manipulations of the medial septal area (MSA) in order to influence the physiology of the septohippocampal pathway and, therefore, the brain functions in which this pathway participates. Aged (22MO) and young (4MO) Fischer-344 rats received microinfusions into the MSA with either saline, the muscarinic agonist, oxotremorine (OXO), or the muscarinic antagonist, scopolamine (SCOP). Working memory was tested in a T-maze spatial alternation task, prior to infusion, immediately after infusion, and 90 min after infusion. Hippocampal theta activity and the population excitatory postsynaptic potential (pEPSP) of the dentate gyrus to perforant path stimulation were recorded immediately following behavioral testing at each of the three time periods. In 22MO rats, intraseptal OXO (0.5 micrograms, 2 micrograms, 5 micrograms) produced a dose-dependent improvement in choice accuracy, a shift of the hippocampal theta peak to a lower frequency and a higher peak power, and an increase in the initial slope of pEPSP. OXO, 0.1 microgram, did not have an effect on behavior or hippocampal physiology and OXO, 10 micrograms, produced an impairment in performance. In 4MO rats, OXO did not affect choice accuracy, nor the pEPSP slope, but altered hippocampal theta peak frequency and power similarly as in 22MO. The lowest behaviorally effective dose, 0.5 microgram OXO, did not influence WM performance when infused into the lateral ventricles (intracerebroventricularly) of either 22MO or 4MO rats. SCOP (2 micrograms, 5 micrograms, 15 micrograms) decreased choice accuracy in a dose-dependent fashion in both 22MO and 4MO rats. However, in 22MO rats, the behavioral dose-response curve for scopolamine was shifted towards greater sensitivity. SCOP produced a shift of the hippocampal theta to a higher frequency and a lower peak power, and a decrease in the initial slope of pEPSP. In 4MO rats, SCOP altered hippocampal theta similarly to 22MO, but did not affect the pEPSP slope. These results indicate that (1) cholinergic receptors in the MSA are a useful target for drugs to improve WM in aging rats, (2) age-related changes in the activity of the septohippocampal pathway may increase its sensitivity to drugs which alter its activity, and (3) alterations in hippocampal physiology may contribute differently to changes in WM in young and in old rats.

Opioid modulation of working memory: intraseptal, but not intraamygdaloid, infusions of beta-endorphin impair performance in spatial alternation.

The effect of beta-endorphin on spatial working memory was examined following microinfusions of beta-endorphin into the medial septal area and central amygdaloid nucleus in Long-Evans male rats. Working memory was assessed by spatial alternation in a T-maze. beta-Endorphin, 250 and 1000 ng/site, respectively, and muscimol, 20 ng/site, were infused into the medial septal area or central amygdaloid nucleus prior to behavioral testing. The hippocampal theta rhythm was examined following intraseptal infusions of beta-endorphin and muscimol. In the medial septal area, beta-endorphin and muscimol impaired choice accuracy and reduced the power of hippocampal theta rhythm. The degree of reduction in the power of hippocampal theta rhythm was correlated with the magnitude of behavioral impairment of choice accuracy in spatial alternation. In the central amygdaloid nucleus, beta-endorphin (1000 ng) and muscimol (20 ng) did not affect choice accuracy. The results suggest that septal, but not amygdaloid, opioid, and GABAergic activity modulate spatial working memory and hippocampal physiology.

Local modulation of basal forebrain: effects on working and reference memory.

The functional roles of the medial septal area (MSA) and nucleus basalis magnocellularis (NBM) in memory were investigated to determine (1) their relative contribution to working and reference memory, (2) their operation in spatial and nonspatial memory, (3) the temporal dynamics of the neural activity within these nuclei as they relate to mnemonic processes, (4) the neurochemical regulation of their activity, and (5) the importance of ACh for their function. Working memory was tested in a continuous conditional discrimination (CCD), and reference memory was tested in the CCD and a sensory discrimination (SD). Bipolar recording electrodes in the dentate hilus monitored hippocampal EEG (theta rhythm). Immediately prior to behavioral testing, trained rats were infused with tetracaine, scopolamine, or muscimol into the MSA or NBM, and the subsequent behavioral and physiological changes were measured and correlated. MSA infusions of all three drugs reduced the power of hippocampal theta and impaired choice accuracy in the CCD; the magnitude of both effects was greater for larger doses and steadily decreased over time after the infusion, producing a strong positive correlation between the power of theta and choice accuracy in the CCD. These infusions had no effect on measures of reference memory in the CCD or in the SD. The results demonstrate that rhythmic activity along the septohippocampal pathway reflects processing of nonspatial working, but not reference memory. NBM infusions did not affect hippocampal theta but did reduce choice accuracy in the SD and completely disrupted performance in the CCD. The NBM appears to have a critical role in both working and reference memory.