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Carolyn W Harley

Publications and source records attributed to Carolyn W Harley.

17 recordsLinked to original sources
PubMed2006

Idazoxan increases perforant path-evoked EPSP slope paired pulse inhibition and reduces perforant path-evoked population spike paired pulse facilitation in rat dentate gyrus.

Norepinephrine, acting via beta-adrenoceptors, enhances the perforant path-evoked potential in dentate gyrus. Using systemic idazoxan to increase norepinephrine, and paired perforant path pulses to probe early inhibition, previous investigators reported that idazoxan increased initial spike amplitude and increased somatic feedback inhibition. Here, feedback inhibition was re-examined in idazoxan-treated (5 mg/kg) rats under urethane anesthesia. To control for initial increased spike amplitude after idazoxan, evoked potentials were matched, pre- and post-idazoxan, on initial population spike. Input-output current profiles were also compared pre- and post-idazoxan. Saline- and timolol-filled micropipettes permitted evaluation of a contribution of local beta-adrenoceptors. As previously observed, initial spike amplitude was potentiated by idazoxan. Comparable spike potentiation was not seen on the timolol micropipette. Paired pulse inhibition of spike amplitude apparently increased, but input-output curve comparisons revealed a loss of feedback facilitation rather than an increase in feedback inhibition. Initial EPSP slopes were depressed after idazoxan in input-output curve data. EPSP slope feedback ratios were significantly reduced following idazoxan. These data suggest idazoxan has multiple effects on perforant path input to the dentate gyrus. Spike potentiation following idazoxan has previously been shown to depend on intact norepinephrine input. Here, the reduction in spike potentiation on the timolol pipette is consistent with other evidence that norepinephrine-mediated potentiation of the perforant path-evoked potential is dependent on local beta-adrenoceptor activation. The input-output data suggest a decrease in feedback facilitation after idazoxan is likely to account for the apparent increase in feedback inhibition previously reported. Decreased EPSP slope ratios with similar paired pulse intervals have been reported in novel environments. Since exposure to novel environments activates locus coeruleus neurons, norepinephrine may mediate the change in EPSP slope inhibition reported in awake rats. In summary, these results are consistent with the hypothesis that idazoxan potentiates granule cell responses to perforant path input in the dentate gyrus via increases in norepinephrine that lead to beta-adrenoceptor activation, and, further, that idazoxan reduces paired pulse feedback spike facilitation and enhances EPSP slope, but not spike, feedback inhibition.

Adrenergic alpha-Antagonists↗
PubMed2005

Glycogen phosphorylase reactivity in the entorhinal complex in familiar and novel environments: evidence for labile glycogenolytic modules in the rat.

Active and total glycogen phosphorylase were measured histochemically in the entorhinal complex of male Sprague-Dawley rats. Rats were sacrificed from their home cage, or after 5 min in a novel holeboard. Hemispheres from each group were paired, sectioned and processed together. Glycogen phosphorylase reactivity highlighted entorhinal cortex in contrast to less densely stained perirhinal cortex or neocortex. The presubiculum, but not parasubiculum, was strongly reactive for glycogen phosphorylase. Within medial and lateral entorhinal cortex, modularity of active glycogen phosphorylase reactivity was apparent. In inner Layer I there were small ( approximately 50 microm) intense patches of active glycogen phosphorylase. In Layer III there were both small and larger ( approximately 200 microm), patches of active glycogen phosphorylase. Lamina dessicans was reactive. Layers V and VI were relatively unreactive. Exposure to a holeboard intensified the small patches of active glycogen phosphorylase in inner Layer I, while attenuating active glycogen phosphorylase reactivity in Layer III. Total glycogen phosphorylase was unaffected by exposure to the novel environment and exhibited a pattern of continuous dense reactivity suggesting enzyme reserves, particularly in superficial layers of entorhinal cortex. These patterns confirm earlier evidence that glycogenolytic demand in Layers I and III of rat entorhinal cortex is organized in a modular fashion and show that such demand can be modified by brief exposure to a novel holeboard.

Animals↗
PubMed2005

Idazoxan activates rat forebrain glycogen phosphorylase in vivo: a histochemical study.

In vitro experiments show norepinephrine activates glycogen phosphorylase and glycogenolysis in forebrain glia. The present study used idazoxan (5 mg/kg) to elevate NE in vivo and examined patterns of active (aGP) and total (tGP) glycogen phosphorylase reactivity in selected neocortical, hippocampal, diencephalic, and striatal sites using a histochemical method. In somatosensory neocortex, aGP reactivity was highest in Layer 4 with consistent reactivity in the barrel fields in vehicle-treated brains. In the hippocampus, the stratum lacunosum moleculare was highly reactive, while cell layers were least reactive. The dentate gyrus and CA3 were more reactive for aGP than CA1. In the diencephalon, the medial habenula was most reactive followed by the reticular nucleus of the thalamus. In the striatum, globus pallidus was most reactive. Reactivity patterns for tGP were similar to those for aGP, but more intense. The neocortex had the highest overall reactivity for tGP. An estimate of the percentage of aGP relative to tGP suggested the regions sampled had similar levels of median basal activation (approximately 65%). Idazoxan increased aGP reactivity in all regions of the neocortex assessed (layers 3-6 of primary and secondary somatosensory cortex and the barrel fields). The neuropil layers, but not the cell layers, of hippocampus were more reactive following idazoxan treatment. Idazoxan also increased aGP reactivity in the laterodorsal, paraventricular, and reticular nuclei of the thalamus. The largest idazoxan-induced changes, as an estimated percentage of tGP, occurred in the hippocampus (approximately 16% for stratum lacunosum moleculare and for CA1 stratum oriens). Increases ranged from approximately 3 to 6% in neocortex and were less than 3% in the diencephalic and striatal areas. These effects of idazoxan are consistent with a role for norepinephrine in activating forebrain glycogenolyis in vivo and supporting increased brain metabolism. They contrast with earlier evidence showing that idazoxan reduces 2-deoxyglucose uptake in these brain areas. Idazoxan, and norepinephrine, may preferentially recruit glycolytic over oxidative metabolism in the rat forebrain.

Adrenergic alpha-Antagonists↗
PubMed2005

Cytotoxic lesions of the hippocampus do not impair social recognition memory in socially housed rats.

Socially housed mice with cytotoxic lesions of the hippocampus do not exhibit social recognition memory 30 min following exposure to a juvenile mouse, however the social recognition memory of singly housed rats is unimpaired. The present study tests the hypothesis that social housing of rats could render social recognition memory hippocampally dependent as seen for mice. Rats were housed with juveniles or with adults. Two social recognition one-animal tests paralleling those used with mice were carried out. Seven social discrimination two-animal tests were also given. Sham operated and hippocampally lesioned rats had normal social memory at 30 min whether socially housed for 24, 48 h, 7 or 8 days prior to testing. These findings support other results indicating the hippocampus proper is not required for normal social memory in rats. In a final experiment, rats socially housed in groups of three since weaning, were tested for 30 min and 24 h social memory. Unlike mice, rats socially housed throughout life exhibited social memory only at 30 min, but not at 24 h. Manipulations that extend social memory in rats may be required to render social memory hippocampally dependent or rats and mice may differ in the neural mediation of social memory.

Animals↗
PubMed2005

Locus ceruleus activation suppresses feedforward interneurons and reduces beta-gamma electroencephalogram frequencies while it enhances theta frequencies in rat dentate gyrus.

The locus ceruleus is activated by novel stimuli, and its activation promotes learning and memory. Phasic activation of locus ceruleus neurons by glutamate enhances the dentate gyrus population spike amplitude and results in long-term potentiation of synaptic responses recorded after 24 h. Cholinergic activation of locus ceruleus neurons increases hippocampal . At the level of the cellular network, it is not clear how the potentiating effects of norepinephrine are mediated. Previous studies show that exogenous norepinephrine enhances inhibitory interneuron firing in the dentate gyrus. This finding appears at odds with evidence for potentiation. In this study, natural release of norepinephrine was induced by glutamate activation of locus ceruleus while we recorded EEGs and physiologically identified interneurons in the dentate gyrus of urethane-anesthetized rats. Feedforward neurons were inhibited (approximately 1-2 min) by locus ceruleus activation. Feedback interneurons showed both increased and decreased activity, whereas granule cells increased firing as predicted by evoked potential studies. EEG results replicated an increase in power (4-8 Hz) with locus ceruleus activation, but the effect with glutamatergic locus ceruleus activation was transient (approximately 1-2 min). Beta-gamma Frequencies were also transiently suppressed. Together, the data suggest that locus ceruleus activation enhances the throughput of concomitant sensory input by reducing feedforward inhibitory interneuron activity, which may reduce "binding" in existing cell assemblies, and enhances the conditions for synaptic plasticity through disinhibition, promotion of 4-8 Hz , and noradrenergic potentiation to facilitate the building of new representations.

Animals↗
PubMed2004

Orexin-A infusion in the locus ceruleus triggers norepinephrine (NE) release and NE-induced long-term potentiation in the dentate gyrus.

The orexins (ORX-A/ORX-B) are neuroactive peptides known to have roles in feeding and sleep. Evidence of dense, excitatory projections of ORX-A neurons to the noradrenergic pontine nucleus, the locus ceruleus (LC), suggests ORX-A also participates in attention and memory. Activation of LC neurons by glutamate produces a beta-adrenergic receptor-mediated long-term potentiation (LTP) of the perforant path-evoked potential in the dentate gyrus, a target structure of the LC that has been implicated in memory. We asked whether ORX-A also activates norepinephrine (NE)-induced LTP by initiating NE release in the hippocampus. Here, we show that ORX-A infusion (0.25-25 fmol) into the LC produces a robust, beta-adrenergic receptor-dependent, long-lasting potentiation of the perforant path-evoked dentate gyrus population spike in the anesthetized rat. Pharmacological inactivation of the LC with an alpha2-adrenergic receptor agonist, before ORX-A infusion, prevents this potentiation. Analysis of NE concentrations in the hippocampus after ORX-A infusion into the LC reveals a transient, but robust, increase in NE release. Thus, this study demonstrates that the dense orexinergic projection to the LC promotes the induction of NE-LTP in the dentate gyrus. ORX-A modulation of LC activity may provide important support for the cognitive processes of attention and memory.

Action Potentials↗
PubMed2004

Olfactory learning in the rat pup: a model that may permit visualization of a mammalian memory trace.

Over the past 10 years considerable insight into intracellular interactions leading to long-term memory formation have been gleaned from various neural circuits within invertebrate and vertebrate species. This review suggests that, while certain intracellular signaling pathways are commonly involved across species, it is important to analyze specific neural systems because critical differences among systems appear to exist. The olfactory bulb has been used by our group to estimate the influence of neuromodulatory systems (serotonin and norepinephrine) on intracellular processes leading to learning. We describe here how activation of noradrenergic input to mitral cells increases cAMP leading to CREB phosphorylation when paired with a conditioning stimulus, odor. CREB phosphorylation is causal in odor preference learning leading to long-term memory for the odor. However, the relationship between cAMP activation and CREB phosphorylation is not straight forward; overstimulation of cAMP pathways impedes learning and prevents CREB phosphorylation. Excessive CREB phosphorylation also interferes with learning.

Animals↗
PubMed2004

Locus ceruleus activation initiates delayed synaptic potentiation of perforant path input to the dentate gyrus in awake rats: a novel beta-adrenergic- and protein synthesis-dependent mammalian plasticity mechanism.

Norepinephrine, acting through beta-adrenergic receptors, is implicated in mammalian memory. In in vitro and in vivo studies, norepinephrine produces potentiation of the perforant path-dentate gyrus evoked potential; however, the duration and dynamics of norepinephrine-induced potentiation have not been explored over extended time periods. To characterize the long-term effects of norepinephrine on granule cell plasticity, the present study uses glutamatergic activation of the locus ceruleus (LC) to induce release of norepinephrine in the hippocampus of the awake rat and examines the subsequent modulation of the dentate gyrus evoked potential for 3 hr (short term) and 24 hr (long term) after LC activation. LC activation initiates a potentiation of the field EPSP slope observed 24 hr later. This late-phase potentiation of the synaptic potential is not preceded by early phase potentiation, although spike potentiation can be seen both immediately after, and 24 hr after, LC activation. Intracerebroventricular infusion of the beta-adrenergic antagonist, propranolol, or the protein synthesis inhibitor, anisomycin, before LC activation blocks the potentiation of perforant path input observed at 24 hr. The initiation of late-phase synaptic potentiation observed at 24 hr but not at the 3 hr after LC activation parallels the observation of a cAMP- and protein synthesis-dependent long-lasting synaptic facilitation in Aplysia that is not preceded by short-term synaptic facilitation. Locus ceruleus-initiated synaptic potentiation may selectively support long-term, rather than short-term, memory. The observation of selective initiation of long-term synaptic facilitation in a mammalian brain, as in invertebrates, is additional evidence that these two forms of memory depend on separable biological mechanisms.

Animals↗
PubMed2004

Norepinephrine and dopamine as learning signals.

The present review focuses on the hypothesis that norepinephrine (NE) and dopamine (DA) act as learning signals. Both NE and DA are broadly distributed in areas concerned with the representation of the world and with the conjunction of sensory inputs and motor outputs. Both are released at times of novelty and uncertainty, providing plausible signal events for updating representations and associations. These catecholamines activate intracellular machinery postulated to serve as a memory-formation cascade. Yet, despite the plausibility of an NE and DA role in vertebrate learning and memory, most evidence that they provide a learning signal is circumstantial. The major weakness of the data available is the lack of a specific description of how the neural circuit modulated by NE or DA participates in the learning being analyzed. Identifying a conditioned stimuli (CS) representation would facilitate the identification of a learning signal role for NE or DA. Describing how the CS representation comes to relate to learned behavior, either through sensory-sensory associations, in which the CS acquires the motivational significance of reward or punishment, thus driving appropriate behavior, or through direct sensory-motor associations is necessary to identify how NE and DA participate in memory creation. As described here, evidence consistent with a direct learning signal role for NE and DA is seen in the changing of sensory circuits in odor preference learning (NE), defensive conditioning (NE), and auditory cortex remodeling in adult rats (DA). Evidence that NE and DA contribute to normal learning through unspecified mechanisms is extensive, but the details of that support role are lacking.

Animals↗
PubMed2003

Early odor preference learning in the rat: bidirectional effects of cAMP response element-binding protein (CREB) and mutant CREB support a causal role for phosphorylated CREB.

Early odor preference learning in rats is associated with increases of phosphorylated CREB (pCREB) in mitral cells of the olfactory bulb. In the present study, herpes simplex virus expressing CREB (HSV-CREB) and dominant-negative mutant CREB (HSV-mCREB) have been injected into the bulb to assess a causal role for CREB and pCREB in this model. Odor paired with stroking or with the beta-adrenoceptor agonist isoproterenol produces odor approach 24 hr later. Isoproterenol-induced learning exhibits an inverted U curve dose-dependent learning relationship with both low and high doses failing to produce learning. pCREB increases have only been seen at the learning effective dose. In the present study, injection of an HSV vector expressing mutant CREB into the olfactory bulb prevented learning induced by stroking. Control HSV expressing LacZ was without effect. Expression of mutant CREB shifted the dose-learning curve for isoproterenol to the right such that a higher dose was required to induce learning. Expression of CREB shifted the dose-learning curve for isoproterenol to the left, with a lower dose now producing learning. As expected from this shift, CREB overexpression interfered with learning induced by stroking. When learning occurred, with either CREB or mutant CREB, pCREB was observed to be elevated relative to the nonlearning LacZ control groups. Unexpectedly, with odor plus stroking in the nonlearning CREB group, the level of pCREB was also higher than with odor plus stroking in LacZ controls that did learn. The data demonstrate a causal role for CREB and pCREB in early mammalian odor preference learning, reinforcing CREB as a "universal" memory molecule. They support evidence that CREB overexpression can be deleterious and suggest the hypothesis of an optimal pCREB window for learning.

Adrenergic beta-Agonists↗
PubMed2003

Two organizational effects of pubertal testosterone in male rats: transient social memory and a shift away from long-term potentiation following a tetanus in hippocampal CA1.

The organizational role of pubertal androgen receptor (AR) activation in synaptic plasticity in hippocampal CA1 and in social memory was assessed. Earlier data suggest pubertal testosterone reduces adult hippocampal synaptic plasticity. Four groups were created following gonadectomy at the onset of puberty: rats given testosterone; rats given testosterone but with the AR antagonist flutamide, present during puberty; rats given testosterone at the end of puberty; and rats given cholesterol at the end of puberty. A tetanus normally inducing long-term potentiation (LTP) was used to stimulate CA1 in the urethane-anesthetized adults during the dark phase of their cycle. Social memory was assessed prior to electrophysiology. Social memory for a juvenile rat at 120 min was seen only in rats not exposed to AR activation during puberty. Pubertal AR activation may induce the reduced social memory of male rats. Early CA1 LTP occurred following tetanus in rats with no pubertal testosterone. Short-term potentiation occurred in rats exposed to pubertal testosterone. Unexpectedly, rats with pubertal AR activation developed long-term depression (LTD). The same pattern was seen in normal male rats. Lack of LTP during the dark phase is consistent with other data on circadian modulation of CA1 LTP. No correlations were seen among social memory scores and CA1 plasticity measures. These data argue for two organizational effects of pubertal testosterone: (1) CA1 synaptic plasticity shifts away from potentiation toward depression; (2) social memory is reduced. Enduring effects of pubertal androgen on limbic circuits may contribute to reorganized behaviors in the postpubertal period.

Androgen Antagonists↗
PubMed2003

Novel objects in a holeboard probe the role of the locus coeruleus in curiosity: support for two modes of attention in the rat.

Idazoxan, an alpha 2 adrenoceptor antagonist (2 mg/kg), enhanced novel object investigation in a holeboard in rats as previously reported (V. Devauges & S. J. Sara, 1990). Two weeks of 10 min/day in 37 degrees C water increased dopamine-beta-hydroxylase staining density in the locus coeruleus but did not enhance novel object investigation. In contrast to idazoxan, however, the warm water treatment increased rearing, center entries, and activity, a pattern previously described during tonic infusion of norepinephrine into the hippocampus. Correlations among dopamine-beta-hydroxylase measures and behavior reinforced these tonic norepinephrine/behavior associations. The behavioral effects across the idazoxan and warm water experiments support G. Aston-Jones et al.'s (1999) 2 modes of attention hypothesis for locus coeruleus function: Phasic locus coeruleus activity promotes focused attention; tonic locus coeruleus activity promotes scanning attention.

Animals↗
PubMed2003

An analysis of response, direction, and place learning in an open field and T maze.

Rats were trained to locate food in a response, direction, or place problem on an open field located at 2 positions. In Experiment 1, both the response and direction groups solved the problem. The place group failed to solve the task in approximately 300 trials. Experiment 2 demonstrated that rats need distinguishable start points to solve a place problem when neither a response nor a direction solution is available. Findings from Experiment 3 suggest that a combination of path traveled and distinct cues help to differentiate start points. Experiment 4 replicated the findings using a T maze. These results suggest "place" solutions are difficult for rats. The data are discussed with respect to conditional learning and modern spatial mapping theory.

Analysis of Variance↗
PubMed2002

Optical imaging of odor preference memory in the rat olfactory bulb.

Early olfactory preference learning in rat pups occurs when novel odors are paired with reinforcing tactile stimulation that activate the noradrenergic locus coeruleus. Pairing of odor and a noradrenergic agonist in the olfactory bulb is both necessary and sufficient for odor preference learning. This suggests the memory change occurs in the olfactory bulb. Previous electrophysiological experiments demonstrated that odor preference training induces an increase in the field excitatory postsynaptic potential to olfactory nerve input and an alteration, after training, in glomerular [14C]2- deoxyglucose uptake and in single-unit responses of principal cells. We investigate here whether, 24 h after olfactory preference training, there is an alteration in intrinsic optical signals at the glomerular level. Six-day-old rat pups were trained, as previously, for a peppermint odor preference. Trained pups and control littermates were subjected to imaging of odor-induced intrinsic optical signals 1 day after the training session. Trained pups exhibited significantly larger responses to the peppermint compared with untrained littermates previously exposed to the same odor. The response of trained pups to a control odor (amyl acetate) was, however, not significantly different from that of untrained littermates. These observations demonstrate that odor preference memory can be read-out by optical imaging techniques.

Animals↗
PubMedDate not supplied

Mitral cell beta1 and 5-HT2A receptor colocalization and cAMP coregulation: a new model of norepinephrine-induced learning in the olfactory bulb.

In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning beta(1)-adrenoceptors activated by the locus coeruleus mediate the unconditioned stimulus, whereas olfactory nerve input mediates the conditioned stimulus, odor. Serotonin (5-HT) depletion prevents odor learning, with 5-HT(2A/2C) agonists correcting the deficit. Our new model proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP). Here, using selective antibodies and immunofluorescence examined with confocal microscopy, we demonstrate that beta(1)-adrenoceptors and 5-HT(2A) receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that beta-adrenoceptor activation by isoproterenol, at learning-effective and higher doses, significantly increases bulbar cAMP, as does stroking. As predicted by our model, the cAMP increases are localized to mitral cells. 5-HT depletion of the olfactory bulb does not affect basal levels of cAMP but prevents isoproterenol-induced cAMP elevation. These results support the model. We suggest the mitral-cell cAMP cascade converges with a Ca(2+) pathway activated by odor to recruit CREB phosphorylation and memory-associated changes in the olfactory bulb. The dose-related increase in cAMP with isoproterenol implies a critical cAMP window because the highest dose of isoproterenol does not produce learning.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Beta1-adrenoceptor or alpha1-adrenoceptor activation initiates early odor preference learning in rat pups: support for the mitral cell/cAMP model of odor preference learning.

We proposed that mitral cell beta1-adrenoceptor activation mediates rat pup odor preference learning. Here we evaluate beta1-, beta2-, alpha1-, and alpha2-adrenoceptor agonists in such learning. The beta1-adrenoceptor agonist, dobutamine, and the alpha1-adrenoceptor agonist, phenylephrine, induced learning, and both exhibited an inverted U-curve dose-response relationship to odor preference learning. Phenylephrine-induced learning occurred in the presence of propranolol to prevent indirect activation of beta-adrenoceptors. Alpha1-adrenoceptor mediation may represent a novel mechanism inducing learning or may increase cAMP in mitral cells via indirect activation of GABA(B) receptors. Neither the beta2-adrenoceptor agonist, salbutamol, nor the alpha2-adrenoceptor agonist, clonidine, induced learning.

Adrenergic alpha-1 Receptor Agonists↗