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No latitudinal differences in adrenocortical stress response in wintering black-capped chickadees (Poecile atricapilla).

Birds respond to deterioration in environmental conditions by elevating their corticosterone levels, which can enhance their survival. It is less clear if animals constantly living in energetically challenging environment show similar increases in adrenocortical function. Previous work has demonstrated that under controlled conditions black-capped chickadees (Poecile atricapilla) from northern latitudes cache more food and perform better on spatial memory tasks than their southern conspecifics. As elevated levels of corticosterone have been shown previously to correlate with spatial memory performance in chickadees, this study aimed to investigate whether black-capped chickadees from northern latitudes have elevated baseline levels of corticosterone and/or a stronger adrenocortical stress response than their southern conspecifics, irrespective of their immediate environment. We found no differences between Alaskan and Colorado chickadees maintained under identical conditions for 3 months in either baseline levels of corticosterone or maximum levels of corticosterone achieved during the stress response. Baseline corticosterone levels were negatively correlated with relative body mass across both groups of birds. Our results suggest that the population differences in food catching behavior and spatial memory were not related to differences in corticosterone levels. We conclude that many reported population differences in baseline levels and in strength of adrenocortical stress response may often reflect differences in local environmental conditions rather than population-specific physiological traits.

Adrenal Cortex↗

Intrahippocampal D-cycloserine improves MK-801-induced memory deficits: radial-arm maze performance in rats.

In order to investigate whether strychnine-insensitive glycine sites coupled with hippocampal NMDA (N-methyl-d-aspartate) receptors are involved in spatial memory in rats, we examined the effects of intrahippocampal treatment of d-cycloserine (DCS), a glycine-site agonist, on spatial-memory deficits which were produced by an NMDA antagonist MK-801 (dizocilpine) on the radial-arm maze task. After the acquisition of this task, the radial-maze performance was tested under the combined treatments of intraperitoneal MK-801 or saline (SAL) and intrahippocampal DCS or SAL. The results showed that MK-801 impaired the performance, and that DCS improved the MK-801-induced performance impairment. These results suggest that glycine sites are involved in spatial memory through their modulatory action on hippocampal NMDA receptors.

Analysis of Variance↗

Reserpine impairs spatial working memory performance in monkeys: reversal by the alpha 2-adrenergic agonist clonidine.

Repeated daily treatment with the catecholamine-depleting agent, reserpine, dramatically reduced performance on the delayed response task, a test of spatial working memory that depends upon the integrity of the prefrontal cortex. Delayed response performance fell from an average of 27.2/30 trials correct before reserpine treatment to an average of 20.4/30 trials correct after repeated reserpine administration. Injection of the alpha 2-adrenergic agonist, clonidine (0.0001-0.05 mg/kg), to chronic reserpine-treated monkeys significantly restored performance on the delayed response task; performance after an optimal dose averaged 27.8/30 trials correct. Clonidine's beneficial effects on delayed response performance were longlasting; monkeys remained improved for more than 24 h after a single clonidine injection. The finding that clonidine is efficacious in reserpinized animals supports the hypothesis that alpha 2-adrenergic agonists improve cognitive function through actions at postsynaptic, alpha 2-adrenergic receptors on non-adrenergic cells. In contrast to the delayed response task, reserpine had little effect on performance of a visual discrimination task, a reference memory task which does not depend on the prefrontal cortex. These results emphasize the importance of postsynaptic, alpha 2-adrenergic mechanisms in the regulation of working memory.

Adrenergic alpha-Agonists↗

Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys.

The effects of systemically administered or iontophoretically applied clonidine (alpha-2 adrenergic agonist) and iontophoretically applied yohimbine (alpha-2 adrenergic antagonist) were examined on prefrontal cortical (PFC) neurons related to spatial working memory (SWM). Systemically administered clonidine (0.04 mg/kg) enhanced SWM-related PFC neuronal activity by 32.5 +/- 14.5%, (mean +/- SD; n = 25 neurons). The facilitatory effect of clonidine was antagonized by iontophoretically applied yohimbine. Iontophoretically applied clonidine enhanced SWM-related PFC neuronal activity by 38.2 +/- 18.6%, (n = 13 neurons), whereas similarly applied yohimbine suppressed it by 34.4 +/- 17.8% (n = 28 neurons). These results indicate that: a) systemically administered clonidine can facilitate SWM-related PFC neuronal activity through actions at alpha-2 adrenoceptors in the PFC; and b) conversely, blockade by yohimbine of alpha-2 adrenoceptors in the PFC suppresses SWM-related neuronal activity. The present study provides neurophysiological evidence that alpha-2 adrenoceptors in the PFC are involved in the cellular mechanisms underlying working memory.

Action Potentials↗

Robust spatial working memory through homeostatic synaptic scaling in heterogeneous cortical networks.

The concept of bell-shaped persistent neural activity represents a cornerstone of the theory for the internal representation of analog quantities, such as spatial location or head direction. Previous models, however, relied on the unrealistic assumption of network homogeneity. We investigate this issue in a network model where fine tuning of parameters is destroyed by heterogeneities in cellular and synaptic properties. Heterogeneities result in the loss of stored spatial information in a few seconds. Accurate encoding is recovered when a homeostatic mechanism scales the excitatory synapses to each cell to compensate for the heterogeneity in cellular excitability and synaptic inputs. Moreover, the more realistic model produces a wide diversity of tuning curves, as commonly observed in recordings from prefrontal neurons. We conclude that recurrent attractor networks in conjunction with appropriate homeostatic mechanisms provide a robust, biologically plausible theoretical framework for understanding the neural circuit basis of spatial working memory.

Action Potentials↗

Neurobehavioural functioning in neonatal intensive care unit graduates in late childhood and early adolescence.

The current study examined memory and executive functioning in a sample of children who were hospital ized in a neonatal intensive care unit (NICU) after birth. Thirty-two children born prematurely and/or with medical complications (NICU children) and 25 control children born at term were assessed with the Cambridge Neuropsychological Testing Automated Battery (CANTAB), a multi-dimensional computer-based measure of memory and executive functioning. Comparisons between the NICU and control groups on the CANTAB subscales indicated that the NICU children had a shorter spatial memory span length and committed more forgetting errors on a spatial working memory task. Correlational analyses demonstrated that the number and extent of medical complications at birth was negatively associated with spatial memory span, planning and spatial recognition memory. Multiple regression models suggested that gestational age was of primary importance in predicting spatial memory span, while neurobiological risk was primary in the prediction of spatial working memory errors. Overall, the current results showed fewer deficits in this group of children than were found in a previous neuropsychological assessment of this cohort. The implications of this finding for discerning the effects of neural plasticity over and above normal brain maturational processes are discussed.

Adolescent↗

Smad-dependent alterations of PPT cholinergic neurons as a pathophysiological mechanism of age-related sleep-dependent memory impairments.

In humans, memory impairments are highly prevalent in the aged population, but their functional and structural origins are still unknown. We hypothesized that circadian rhythm alterations may predict spatial memory impairment in aged rats. We demonstrate an association between sleep/wake circadian rhythm disturbances (non-REM sleep fragmentation) and spatial memory impairments in aged rats. We show by light and electron microscopy that these age-related disruptions in circadian rhythm and spatial memory are also associated with degeneration of cholinergic neurons of the pedunculopontine nucleus (PPT), a structure known to be involved in sleep and cognitive functions and which is altered during aging. Finally, we demonstrate that a trophic deregulation of the PPT occur in aged impaired rats, involving an over activation of the TGFbeta-Smad cascade, a signalling pathway involved in neurodegeneration. In conclusion these results provide a new pathophysiological mechanism for age-related sleep-dependent memory impairments opening the ground for the development of new therapeutic approaches of these pathologies.

Aging↗

Determinants of non-spatial working memory deficits in rats given intraventricular infusions of the NMDA antagonist AP5.

Two series of experiments using rats assessed the effects of intraventricular administration of the NMDA antagonist AP5 on performance of non-spatial working memory tasks. The first series used a continuous delayed non-matching to sample (DNMS) design; the second series used a discrete trial delayed matching to sample (DMS) design. Performance was assessed at retention intervals ranging from approximately 5 to 90 sec. The subjects had acquired the behavioural tasks before drug testing commenced. In the DNMS series, minipumps containing vehicle, 5, 10 or 15 nM D-AP5 were implanted. Every 10 days, each rat's minipump was removed and replaced with a fresh pump containing a new drug dose in a counterbalanced design, so that all rats were tested under all four conditions. There were no drug effects on performance at any retention interval. In the DMS series, there were three different basic task variants. Minipumps filled either with 15 mM D-AP5 or vehicle solution were implanted. Vehicle rats performed at approximately pre-operative levels; AP5 rats were impaired only on task variants using repeated stimulus presentations within session. There was no interaction between retention interval and drug treatment. This pattern of results closely resembles that seen following hippocampectomy or fornicotomy, as would be expected if this drug, administered intraventricularly, selectively affected hippocampal function.

2-Amino-5-phosphonovalerate↗

Movement-associated neural excitation as a factor in spatial representational memory in rats.

The hypothesis that rats require an attention like function arising from integration of exteroceptive and movement-related excitation during the information phase of representational memory-dependent discriminations is proposed. Experiments 1A and 1B (both behavioral) demonstrated the crucial importance of movement-related excitation (angle of turn at T-maze choice point). Experiment 2 showed that, contrary to plausible expectations, ablation of putative posterior parietal association cortex only mildly affected memory. This finding agrees with the notion of a nonspecific mass action-equipotential effect of ablations in nondifferentiated cortex on memory rather than the specific effects resulting from dorsolateral prefrontal ablations in primates. Instead, it is proposed from previous data that the hippocampus integrates movement-related and exteroceptive excitations necessary for representational memory, which is largely restricted to spatial attributes in rats.

Animals↗

The development of memory for location: what role do spatial prototypes play?

Two experiments investigated the role of spatial prototypes in estimates of location. In Experiment 1 (N = 144), children and adults learned the locations of 20 objects in an open, square box designed to look like a model house. In two conditions, opaque lines or walls divided the house into four regions, and in the other condition, no boundaries were present. Following learning, the dots marking the locations were removed, and participants attempted to replace the objects. Children and adults overestimated distances between target locations in different regions. Contrary to Huttenlocher, Hedges, and Duncan's hierarchical theory of spatial memory, none of the groups displaced the objects toward the region centers. In Experiment 2 (N = 96), boundaries were removed during testing to determine whether children and adults were more likely to displace objects toward region centers when uncertainty about location increased. Again, all age groups overestimated distances between target objects in different regions. In addition, adults and 11-year-olds in the most salient boundary condition displaced objects toward the region centers. Discussion focuses on the implications of these results for understanding how children and adults estimate location.

Adult↗

Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex.

Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10- and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits.

Animals↗

Effects of long-term restricted feeding on radial maze performance by aged rats.

Rats were fed every other day (EOD) from 3-21 months of age prior to training in an 8-arm radial maze with retention intervals of 0, 1 or 5 hr imposed between the fourth and fifth choices. Their performance was compared to that of another aged group fed ad lib throughout life prior to radial maze training and to 3 month old controls. Rats fed ad lib until training adapted to the maze more slowly than young controls and were impaired in acquiring accurate spatial memory. EOD feeding eliminated age-related differences in the initial rate of adaptation to the radial maze but had no effect on the development of accurate spatial memory at any of the retention intervals. These results indicate that differences in deprivation history are probably not responsible for previous findings that radial maze training early in life prevents the appearance of age-related deficits in accurate spatial memory.

Aging↗

Differential anterior prefrontal activation during the recognition stage of a spatial working memory task.

Neuroimaging studies commonly show widespread activations in the prefrontal cortex during various forms of working memory and long-term memory tasks. However, the anterior prefrontal cortex (aPFC, Brodmann area 10) has been mainly associated with retrieval in episodic memory, and its role in working memory is less clear. We conducted an event-related functional magnetic resonance imaging study to examine brain activations in relation to recognition in a spatial delayed-recognition task. Similar to the results from previous findings, several frontal areas were strongly activated during the recognition phase of the task, including the aPFC, the lateral PFC and the anterior cingulate cortex. Although the aPFC was more active during the recognition phase, it was also active during the delay phase of the spatial working memory task. In addition, the aPFC showed greater activity in response to negative probes (non-targets) than to positive probes (targets). While our analyses focused on examining signal changes in the aPFC, other prefrontal regions showed similar effects and none of the areas were more active in response to the positive probes than to the negative probes. Our findings support the conclusion that the aPFC is involved in working memory and particularly in processes that distinguish target and non-target stimuli during recognition.

Adult↗

The enhancing effects of hippocampal infusions of glucose are not restricted to spatial working memory.

Extensive evidence shows that hippocampal infusions of glucose enhance spontaneous alternation (SA) performance or reverse deficits in this task. The current experiments determined whether the enhancing effects of hippocampal infusions of glucose are restricted to spatial working memory. Specifically we tested whether hippocampal infusions of glucose would reverse deficits in an emotional reference memory task (continuous multiple trial inhibitory avoidance [CMIA]) produced by septal infusions of the gamma-aminobutyric acid agonist muscimol. Male Sprague-Dawley rats were given septal infusions of vehicle or muscimol (0.15 nmol: SA; 5 nmol: CMIA) combined with hippocampal infusions of vehicle or glucose (50 nmol) 15 min prior to assessing SA or CMIA training. CMIA retention was tested 48 h later. Muscimol infusions decreased percent alternation scores and avoidance retention latencies. Importantly, hippocampal infusions of glucose reversed the deficits produced by the septal muscimol infusions on both tasks. These findings show for the first time that hippocampal glucose infusions also influence emotional memory, indicating that the enhancing effects of glucose generalize to memory tasks that vary in motivational and cognitive demand.

Animals↗

Verbal and spatial working memory in older individuals: A positron emission tomography study.

Recent reviews of a substantial number of studies have partially resolved questions concerning the brain regions used by working memory for manipulation and representation. We report a large single experiment in middle-aged to older adults (n = 89), classified by hypertensive status. Our design addresses the question of regions related to manipulation and representation, most particularly comparing spatial and verbal working memory. A control, memory search, and 2-back running memory task were performed with identical stimuli and responses during whole-brain 15O water positron emission tomography (PET) scans. Letter or spatial position instructions created verbal or spatial working memory versions of the tasks. We assessed agreement with the literature using regions of interest that were defined by clusters of activation empirically derived from the literature by Wager and Smith (Wager, T.D. and Smith, E.E., Neuroimaging studies of working memory: a meta-analysis, Cognitive, Affective and Behavioral Neuroscience, 3 (2003) 255-274). Our results largely confirmed conclusions from the review on the organization of working memory into dorsal prefrontal manipulation and ventrolateral prefrontal maintenance areas and representation in dorsal and ventral paths. Specific verbal versus spatial comparisons were also concordant with prior work establishing posterior lateralized representation for different contents by working memory. The similarity of results between this older sample and results derived by others from younger participants is notable.

Aged↗

Stability of spatial working memory across the estrous cycle of Long-Evans rats.

In the adult rat, hippocampal dendritic synaptic connectivity in region CA1 fluctuates across the estrous cycle. This study examined the potential functional impact of such fluctuations on spatial working memory in regularly cycling Long-Evans rats. Rats were trained in a delayed non-match-to-sample radial-arm maze task and performance was monitored across the estrous cycle. There were no significant alterations in the acquisition or performance of the working memory task across the estrous cycle, with 1- or 4-h delays imposed between training and testing sessions. However, rats performed the task significantly more slowly on proestrus than on any other estrous cycle day under both delay conditions. These results indicate that while working memory remains stable, sensorimotor or motivational aspects of the performance of this radial-arm maze task may vary across the estrous cycle.

Animals↗

fMRI response to spatial working memory in adolescents with comorbid marijuana and alcohol use disorders.

Alcohol and marijuana use are prevalent in adolescence, yet the neural impact of concomitant use remains unclear. We previously demonstrated functional magnetic resonance imaging (fMRI) response to spatial working memory (SWM) among teens with alcohol use disorders (AUD) compared to controls, and predicted that adolescents with marijuana and alcohol use disorders would show additional abnormalities. Participants were three groups of 15-17-year-olds: 19 non-abusing controls, 15 AUD teens with limited exposure to drugs, and 15 teens with comorbid marijuana and alcohol use disorders (MAUD) and minimal other drug experience. After >2 days' abstinence, participants performed a SWM task during fMRI acquisition. fMRI brain response patterns differed between groups, despite similar performance on the task. MAUD youths showed less activation in inferior frontal and temporal regions than controls, and more response in other prefrontal regions. Compared to AUD teens, MAUD youths also showed less inferior frontal and temporal activation, but more medial frontal response. Overall, MAUD youths showed different brain response abnormalities than teens with AUD alone, despite relatively short histories of substance involvement. This pattern could suggest compensation for marijuana-related attention and working memory deficits. However, relatively recent use and premorbid features may influence results, and should be examined in future studies.

Adolescent↗

The effects of ethanol and silymarin treatment during gestation on spatial working memory.

BACKGROUND: Using a rat model we have found that the bioflavonoid silymarin (SY) ameliorates some of the negative consequences of in utero exposure to ethanol (EtOH). In the current study our aim was to determine if spatial working memory (SWM) was impaired in offspring whose mothers were maintained on a liquid diet containing EtOH during different gestational weeks. We also determined if SWM was altered with a concomitant administration of SY with EtOH during specific gestational weeks. METHODS: We provided pregnant Fischer/344 rats with liquid diets containing 35% EtOH derived calories (EDC) during specific weeks of the gestational period. A silymarin/phospholipid compound containing 29.8% silybin co-administered with EtOH was also administered during specific weeks of the gestational period. We tested SWM of the offspring with a radial arm maze on postnatal day (PND) 60. After testing the rats were sacrificed and their brains perfused for later analysis. RESULTS: We observed SWM deficits, as well as a significantly lower brain weight in female offspring born of mothers treated with EtOH during the third week of gestation in comparison to mothers treated during either the first or second weeks of gestation. Rats from any group receiving EtOH in co-administration with SY showed no significant deficits in SWM. CONCLUSION: EtOH treatment during the last week of gestation had the greatest impact on SWM. The addition of SY to the EtOH liquid diet appeared to ameliorate the EtOH-induced learning deficits.

Animals↗