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Exploratory drive, frontal lobe function and adipsia in aging.

Aging in animals in accompanied by a decrease in exploratory drive, as assessed by hole poking and spontaneous alternation tests. This decrease is caused either by increased fear of the novel testing environment (neophobia) or by apathy. Either cause may be related to dysfunction of prefrontal cortex-related pathways. The myelination of the prefrontal cortex appears late in ontogeny. In accordance to the last-in first-out principle, this brain region seems to be affected early during aging. It remains to be determined whether this decrease of exploratory behavior is reversible by behavioral intervention, by dietary changes or by the administration of psychotropic drugs. One hypothesis worth testing is whether the decrease in exploration is associated to the well-described adipsia in human aging, whose neurobiological basis has not yet been determined. It is possible to consider that the maladaptive response to thirst is responsible for some senescent changes in the brain and that reversal of adipsia by behavioral, dietary or pharmacological means improves the quality of life in the elderly.

Affect↗

Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment.

Neurons are continually born from endogenous stem cells and added to the dentate gyrus throughout life, but adult hippocampal neurogenesis declines precipitously with age. Short-term exposure to an enriched environment leads to a striking increase in new neurons, along with a substantial improvement in behavioral performance. Could this plastic response be relevant for explaining the beneficial effects of leading "an active life" on brain function and pathology? Adult hippocampal neurogenesis in mice living in an enriched environment from the age of 10 to 20 months was fivefold higher than in controls. Relatively, the increase in neuronal phenotypes was entirely at the expense of newly generated astrocytes. This cellular plasticity occurred in the context of significant improvements of learning parameters, exploratory behavior, and locomotor activity. Enriched living mice also had a reduced lipofuscin load in the dentate gyrus, indicating decreased nonspecific age-dependent degeneration. Therefore, in mice signs of neuronal aging can be diminished by a sustained active and challenging life, even if this stimulation started only at medium age. Activity exerts not only an acute but also a sustained effect on brain plasticity.

Aging↗

Responses to stress and novelty in adult rats born vaginally, by cesarean section or by cesarean section with acute anoxia.

The aim of this study was to test the hypothesis that alterations in birth conditions, specifically vaginal birth vs. birth by Cesarean section (C-section) vs. birth by C-section with an added period of acute global anoxia, produces long-term differences in behavioral responses to stress or novelty in the rat at adulthood. In comparison to animals born by rapid C-section alone, animals born by C-section with 10 or 15 min of added anoxia were significantly more immobile during forced swim stress administered for 6 trials over several weeks. In a step-down passive avoidance task, there were no group differences in acquisition or retention of the avoidance response. However, when initially placed in the passive avoidance apparatus before delivery of shock, animals born by C-section with 15 min of anoxia required significantly more pretrials to step down from the wooden platform, than did vaginally born or C-sectioned animals. No group differences were observed on measures of exploratory behavior in an elevated plus-maze or of approach behavior either to food or to a novel object in an open field. These findings suggest that birth conditions which include a degree of perinatal hypoxia can contribute to variability in selective responses to stress and novelty in the adult rat.

Acute Disease↗

Prenatal cocaine exposure specifically alters spontaneous alternation behavior.

Our laboratory has previously characterized a rabbit model of gestational cocaine exposure in which permanent alterations in neuronal morphology, cell signaling and psychostimulant-induced behavior are observed. The cellular and molecular neuroadaptations produced by prenatal cocaine occur in brain regions involved in executive function and attention, such as the anterior cingulate and medial prefrontal cortices. Therefore, in the present study, we have measured the effects of prenatal cocaine exposure on specific behavioral tasks in adult offspring whose mothers were treated with cocaine (3mg/kg, twice a day, E16-E25). We assessed non-spatial, short-term memory in a two-object recognition task and found no deficits in memory or exploratory behaviors in cocaine-exposed offspring in this paradigm. We also evaluated a different memory task with a more robust attentional component, using spontaneous alternation in a Y maze. In this task, young adult rabbits exposed to cocaine prenatally exhibited a significant deficit in performance. Deficits in spontaneous alternation can be induced by a wide variety of behavioral and cognitive dysfunctions, but taken together with previous findings in this and other animal models, we hypothesize that prenatal exposure to cocaine alters highly specific aspects of cognitive and emotional development.

Animals↗

Acute effect of an extract of Ambrosia paniculata (Willd.) O. E. Schultz (mugwort) in several models of experimental epilepsy.

The acute effect of Ambrosia paniculata was studied in several animal models of epilepsy. Intraperitoneal injections (0.01 mL/g body wt) of a decoction of the dry leaves significantly enhanced the latency to the first convulsion and survival time in mice injected with picrotoxin (7 mg/kg) or isoniazid (210 mg/kg). Epileptic spikes were induced by topical application of penicillin through a glass electrode filled with a penicillin-agar-saline mixture and recorded in sensorimotor and occipital cortices, in rats immobilized with d-tubocurarine. The plant decoction reduced significantly the spike amplitude in both sites. The mentioned effects were elicited at doses that also reduced general motor activity (Irwin test) and exploratory behavior. The decoctions were not effective against electroshock-induced convulsions in mice. The convulsions induced by isoniazid, picrotoxin, and penicillin differed from those induced by electroshock implicating selective disruption of GABAergic neurotransmission. The results suggest that A. paniculata, like several conventional antiepileptic drugs, might act by enhancing GABAergic neurotransmission, a hypothesis that requires further demonstration. These results explain and justify the traditional use of the plant in epilepsy.

Ambrosia↗

Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior.

Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.

Animals↗

Tactile responses in the granule cell layer of cerebellar folium crus IIa of freely behaving rats.

We recorded activity from the granule cell layer (GCL) of cerebellar folium Crus IIa as freely moving rats engaged in a variety of natural behaviors, including grooming, eating, and free tactile exploration. Multiunit responses in the 1000-4500 Hz range were found to be strongly correlated with tactile stimulation of lip and whisker (perioral) regions. These responses occurred regardless of whether the stimulus was externally or self-generated and during both active and passive touch. In contrast, perioral movements that did not tactually stimulate this region of the face (e.g., chewing) produced no detectable increases in GCL activity. In addition, GCL responses were not correlated with movement extremes. When rats used their lips actively for palpation and exploration, the tactile responses in the GCL were not detectably modulated by ongoing jaw movements. However, active palpation and exploratory behaviors did result in the largest and most continuous bursts of GCL activity: responses were on average 10% larger and 50% longer during palpation and exploration than during grooming or passive stimulation. Although activity levels differed between behaviors, the position and spatial extent of the peripheral receptive field was similar over all behaviors that resulted in tactile input. Overall, our data suggest that the 1000-4500 Hz multiunit responses in the Crus IIa GCL of awake rats are correlated with tactile input rather than with movement or any movement parameter and that these responses are likely to be of particular importance during the acquisition of sensory information by perioral structures.

Action Potentials↗

Acquisition of a spatial conditioned place preference is impaired by amygdala lesions and improved by fornix lesions.

This experiment examined the role of the lateral nucleus of the amygdala, the hippocampus and the dorsal striatum in the acquisition of a conditioned place preference (CPP). The CPP was established on a radial maze which was rotated before each daily trial so that only distal cues could be used to distinguish among locations on it. Each rat was assigned a paired location in which the arm contained food, and an unpaired location in which the arm was empty. A training trial consisted of 30-min confinements in the paired and unpaired locations on successive days. Groups of animals received between 1 and 4 training trials, after which they were tested for their preference between their two assigned locations with no food in either one. Normal animals acquired a CPP after 4 training trials, an instance of stimulus--reward learning. Electrolytic and neurotoxic lesions of the lateral nucleus of the amygdala prevented acquisition of the CPP in 4 training trials, suggesting that some function of this structure (or of a neural system that includes it) is required for acquisition and/or expression of stimulus--reward associations. Striatal lesions had no effect on the CPP. Fornix lesions facilitated acquisition of the CPP after 1-3 training trials, but no CPP was observed in animals with combined fornix and amygdala lesions, suggesting that exposure to the maze environment led to the processing of information in a hippocampal system that interfered with acquisition or expression of the amygdala-based CPP. Fornix lesions also increased the number of entries into maze arms on the test day, and concurrent amygdala lesions attenuated this increase. This finding suggests that the increase in arm entries may have been generated by the amygdala and suppressed by the hippocampus. Arm entries were interpreted as an instance of a particular type of exploratory behavior. Therefore, the present results suggest that a neural system including the lateral nucleus of the amygdala mediates both stimulus--reward learning and at least one form of exploration, possibly through its connections with the motor output system in ventral striatum. A hippocampal system appears to suppress or interfere with both of these behaviors in normal animals.

Amygdala↗

The effects of prenatal methylazoxymethanol acetate (MAM) on holeboard exploration and shuttle avoidance performance in rats.

Forty pregnant rats were given an IP injection of either 0, 14, 22, or 30 mg/kg of MAM on day 15 of gestation. One animal of each sex from each litter was tested between 80 and 90 days of age in a holeboard mounted on a stabilimeter. An additional animal of each sex from each litter was tested between 110 and 120 days of age in a two-way shuttle avoidance task. In the holeboard task, prenatal treatment with MAM resulted in an increased frequency of dipping which was accompanied by an increased number of transitions between holes, rather than stereotypy. Altered patterns of exploratory behavior over the course of the test session were also evident in MAM treated offspring as compared to controls. The 22 mg/kg group tended to show less of a decrease in their activity levels over the course of the session than the other groups. In the shuttle avoidance task, prenatal treatment with MAM resulted in a facilitation of avoidance performance as compared to controls. In addition, increased activity (as measured by intertrial interval crossings) was evident in MAM treated offspring, while escape latencies were equivalent across the groups. However, the pattern of results suggest that the facilitated avoidance performance cannot be accounted for by the increased activity. These results are discussed in terms of various hypothesis which may account for the behavioral deficits shown by MAM treated offspring.

Animals↗

Overexpression of hippocampal Ca2+/calmodulin-dependent protein kinase II improves spatial memory.

Hippocampal alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII) has been implicated in neuronal plasticity and spatial learning. In the present experiment, an adeno-associated virus (AAV) vector was designed to express alphaCaMKII driven by the U6 promotor. Microinfusion of this vector into the rat hippocampus increased alphaCaMKII immunoreactivity by approximately 73% (Western analysis) and improved performance in a water maze task. Locomotor activity and exploratory behavior in an open field task were not altered by the overexpression of alphaCaMKII. These data support a role for alphaCaMKII in spatial or explicit memory storage. The advantages of viral vectors for manipulating target proteins expression compared with genetically modified mouse models are discussed.

Animals↗

Activation of the brain 5-HT2C receptors causes hypolocomotion without anxiogenic-like cardiovascular adjustments in mice.

The present study evaluated whether hypolocomotion elicited by subcutaneous administration of the non-specific 5-HT/preferential 5-HT(2C) receptor agonist mCPP during novelty exposure was due to an enhanced anxiety-like state. The effects of mCPP on exploratory behavior during exposure to a new environment (novelty) were studied in male C57BL/6N mice. Subcutaneous injection of mCPP (1 and 3mg/kg) and the preferential 5-HT(2C) receptor agonist MK212 (0.7 and 1mg/kg) induced hypolocomotion during novelty exposure. The selective 5-HT(2C) receptor antagonist SB242084 (0.3mg/kg) reversed the mCPP-induced hypolocomotion into hyperlocomotion. In contrast, MK212 induced hypolocomotion that was blocked by SB242084, indicating a specific 5-HT(2C) receptor involvement. When injected intracerebroventricularly, mCPP (30microg) elicited hypolocomotion, whereas the same dose mildly increased locomotion when injected into the dorsal hippocampus. Since anxiety affects autonomic functions, effects of mCPP on cardiovascular function were studied by radio-telemetry in the home cage of unrestrained mice. Subcutaneous injection of mCPP (3mg/kg) had no significant effect on heart rate and mean arterial blood pressure. In summary, in view of lack of autonomic effects, and the lack of hypoactivity upon forebrain stimulation, the hypolocomotion induced by systemic mCPP cannot be explained by an enhanced anxiety-like state.

Animals↗

[The effect of lesions of the anteroventral and anterodorsal thalamic nuclei on the emotional reactivity of the rat].

The effect of anteroventral and anterodorsal thalamic nuclei lesions on emotional reactivity has been studied. The behavior of 18 rats (half of them bearing thalamic lesions) was studied by means of the open field and the acquisition of a conditioned emotional response (Estes and Skinner technique). Results show that no differences between control and experimental animals were found in exploratory behavior in the open field, where the number of defecations in each group was similar. They also show great impairment in the acquisition of a conditioned emotional response in experimental animals. These results suggest that the structures under study might be involved in the regulation of emotional reactivity.

Animals↗

Altered behavior and alcohol tolerance in transgenic mice lacking MAO A: a comparison with effects of MAO A inhibitor clorgyline.

The influence of deficiency of monoamine oxidase A (MAO A) gene and the lack of enzyme MAO A on the behavior of transgenic mouse strain (Tg8) was studied. It was shown that MAO-A-lacking mice differed from mice of the wild-type strain C3H/HeJ (C3H) by an attenuated acoustic startle response, prepulse inhibition (PPI) was unchanged. In Tg 8 mice, the exploratory nose-poking in the holeboard test as well as exploratory line crossing in the "light-dark" test were decreased. No effect of MAO A deficiency on locomotor activity was found. No alcohol preference or difference between Tg8 and C3H in ethanol consumption in the free-choice test has been found, although an increase in alcohol tolerance has been demonstrated. Ethanol-induced (0.3 g/100 g ip) sleep latency was longer, duration of sleep was shorter and ethanol hypothermia was reduced in MAO-A-lacking mice. Comparison of effects of MAO A knockout with those of irreversible MAO A inhibitor clorgyline (5 and 10 mg/kg ip) on C3H mice showed a similar reducing effect on ethanol-induced sleep, but potentiated ethanol-induced hypothermia. Clorgyline administration provoked a tendency to decrease of exploratory activity in the nose-poking test and decreased the frequency of exploratory rearings in the light-dark test. Clorgyline (5 and 10 mg/kg) did not affect the acoustic startle response, but a dose of 5 mg/kg diminished PPI. Therefore, Tg8 mice exhibited a decreased startle response and exploratory activity and an increased tolerance to ethanol. A similar increase in tolerance to ethanol-induced sleep and a tendency to decrease exploratory behavior were displayed by clorgyline. Other effects on behavior were different, suggesting the influence of long-lasting action of MAO A knockout and the involvement of a compensatory mechanism in Tg8 mice.

Alcohol Drinking↗

Glia mechanisms in mood regulation: a novel model of mood disorders.

INTRODUCTION: Recent evidence in clinical and preclinical studies has implicated glutamate neurotransmissions in pathophysiology of mood disorders. The regulation of amino acid neurotransmission, i.e., glutamate and gamma-aminobutyric acid (GABA) involves coordinated mechanisms of uptake and transport within a tripartite synaptic system that includes neurons and glia. Newly appreciated role of the glia, more specifically astrocytes on neuronal functions combined with reported postmortem abnormalities of glia in patients with mood disorders further supports the role of glia in mood disorders. MATERIALS AND METHODS: This report presents some of our preliminary results utilizing glia-selective toxins and other pharmacological tools to suppress glial function within the limbic system to study the resulting behavioral abnormalities, and thus, elucidate glial involvement in the development of mood disorders. RESULTS AND DISCUSSION: We demonstrate that chronic blockade of glutamate uptake by a glial/neuronal transporter antagonist L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) within the amygdala, a key area implicated in mood regulation, results in dose-dependent reduction in social exploratory behavior and disrupts circadian activity patterns consistent with symptoms of mood disorders. Similarly, the selective astrocytic glutamate transporter type 1 (GLT-1) blocker dihydrokainic acid (DHK) injected into the amygdala also results in reduced social interaction that is blocked by selective glutamate N-methyl-D-aspartate (NMDA) type receptor antagonist AP5. The results are discussed in the context of glial and glutamate mechanisms in mood disorders and potential therapeutic avenues to address these mechanisms.

Affect↗

Contribution of stress and gender to exploratory preferences for familiar versus unfamiliar conspecifics.

An apparatus for measuring the exploratory preferences of rats for familiar and unfamiliar conspecifics in a novel environment was designed. The exploratory behavior of males and females was compared and contrasted to that elicited in response to an acute aversive event. Sprague-Dawley male and female rats were exposed to restraint and 60, 1 s, 1 mA tailshocks and returned to their home cage. Either 2 or 24 h later, they were placed in a novel environment with a familiar cage-mate and an unfamiliar conspecific of the same sex. Relative to unstressed controls and females, males stressed 2 h previously decreased the exploration of the unfamiliar conspecific, exhibiting a rapid decrease over the course of the trial. In response to the stressor, however both sexes, however, decreased the exploration of the familiar conspecific, decreased their overall activity, and returned preferentially to their starting quadrant. None of these stress-induced effects were evident 24 h later upon the first or second exposure to the apparatus. Thus, exposure to the stressor transiently increased perseveration and decreased activity in males and females, but only decreased the exploration of novel conspecifics in males. These results indicate that a number of behavioral responses to stressors are conserved across gender, but those relating to novelty are more pronounced in males.

Animals↗

Interaction between neuropeptide Y and alpha-melanocyte stimulating hormone in amygdala regulates anxiety in rats.

Neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (alpha-MSH) have been implicated in pathophysiology of feeding and certain mood disorders, including anxiety and depression. Both the peptides are abundantly present in CNS, especially in the hypothalamus and amygdala. Although they are known to exert opposite effects, particularly with reference to anxiety, the underlying mechanisms are not known. We were interested in studying the interaction between these two peptides in the regulation of anxiety, within the framework of amygdala. We administered agents like NPY, alpha-MSH, selective melanocortin-4 receptor (MC4-R) antagonist HS014 and NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY, alone and in combinations, unilaterally in right amygdala of rats and measured the response using elevated plus maze test. While NPY and [Leu(31), Pro(34)]-NPY increased the time spent and number of entries in the open arms suggesting anxiolytic-like effects, alpha-MSH resulted in opposite responses. Anxiolytic-like effect of NPY (10 nM) or [Leu(31), Pro(34)]-NPY (5 nM) was significantly reduced following prior alpha-MSH (250 ng) administration. Co-administration of HS014 (1 nM) and NPY (5 nM) or [Leu(31), Pro(34)]-NPY (1 nM) at subeffective doses evoked synergistic anxiolysis. Since the closed arm entries displayed by animals of all the groups were in a similar range, the effects might not be ascribed to the changes in general locomotor activity. These results suggest that endogenous alpha-MSH and NPY containing systems may interact in the amygdala and regulate exploratory behavior in an animal model of anxiety.

Amygdala↗

Orphan neuropeptide NocII, a putative pronociceptin maturation product, stimulates locomotion in mice.

NocII is a heptadecapeptide whose sequence lies immediately downstream of nociceptin, the newly discovered natural agonist of the ORL1 receptor, in pronociceptin, nociceptin's precursor polypeptide. Since the sequence of NocII is framed by putative convertase excision sites and it totally conserved across murine and human species, we have sought to determine whether this orphan neuropeptide might by physiologically significant, i.e. endowed with central biological activity in vivo. Intracerebroventricular administration of 10 and 100 ng of NocII increased locomotion in mice. However, unlike nociceptin, which stimulates both the horizontal and vertical (rearing) components of locomotion, NocII affected only the horizontal component. The motor stimulant action of NocII appears to depend largely on dopamine transmission since it is totally reversed by the D1 or the D2 dopamine receptor antagonists SCH 23390 and haloperidol. NocII does not modify the number of explored holes in the hole board test, indicating that, unlike nociceptin, the orphan peptide does not affect exploratory behavior in mice.

Amino Acid Sequence↗

Rats do react to stimulus omission.

1. The great majority of data supporting the hypothesis of a system capable of comparing current sensorial inputs with an internal representation of the environment comes from studies about exploratory activity to new stimuli or to manipulation of features of a familiar stimulus. On the other hand, these data could also be explained simply by arousal constructs. In this context, demonstrations of exploratory behavior to the absence of a previously presented stimulus (i.e., stimulus omission) would provide stronger support for the idea of a comparator. 2. To test the reaction of rats to the absence of a stimulus, rats were submitted to 7 exploratory trials in an open-field. In the 1st trial there were only two patterns on the apparatus wall. In trials 2-6 a stimulus was presented in a designated area of the field. Finally, in the 7th trial this stimulus was omitted. Results showed that the animals reacted to the stimulus omission by spending more time in the stimulus presentation place during the 7th trial than 1) in the 1st trial (also without stimulus), 2) in the 6th trial (last trial with a stimulus present), and 3) in 3 neutral sectors of the same size as the stimulus presentation place, during the 7th trial. 3. These data indicate that rats do react to the absence of a familiar stimulus and provide strong support for the existence of a Comparator System since the rats responded to "something that wasn't there anymore", a response that could only be due to a reaction triggered by a mismatch between internal representation of the environment and its present state.

Analysis of Variance↗