Carolyn W. Harley

A role for norepinephrine in arousal, emotion and learning?: Limbic modulation by norepinephrine and the kety hypothesis

1. Kety hypothesized that forebrain norepinephrine acted to selectively enhance cell firing in neurons receiving environmental inputs during affectively important events. He further suggested that norepinephrine could act to induce a persistent facilitation of the inputs which accompany affectively important events and would thus promote a memory for these events. 2. The electrophysiological actions of norepinephrine at the time Kety proposed his hypothesis were thought to be inhibitory. More recent evidence has demonstrated that norepinephrine in neocortex and cerebellum enhances both excitatory and inhibitory evoked activity much as Kety proposed. This has been termed norepinephrine neuromodulation. 3. The locus coeruleus-norepinephrine system which gives rise to neocortical and cerebellar norepinephrine innervation also innervates, even more densely, areas of the limbic system. A review of norepinephrine actions, particularly in limbic cortex, indicates that locus coeruleus-norepinephrine also enhances transmission of evoked inputs in these structures. 4. A long-lasting enhancement of evoked inputs by locus coeruleus-norepinephrine has been demonstrated in the hippocampus. This long-lasting enhancement of inputs is reviewed in detail since it appears to directly support Ketys hypothesized persistent facilitation effect of norepinephrine. It is suggested that norepinephrine-induced long-lasting enhancement may underlie numerous demonstrations of norepinephrine-dependent memory and neural plasticity in the forebrain. 5. The relationship of norepinephrine neuromodulation to possible candidate mechanisms and to activation of specific norepinephrine receptors is briefly discussed.

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.

Cognitive rehabilitation reduces cognitive impairment and normalizes hippocampal CA1 architecture in a rat model of vascular dementia.

Dementia is a major cause of morbidity in the western society. Pharmacological therapies to delay the progression of cognitive impairments are modestly successful. Consequently, new therapies are urgently required to improve cognitive deficits associated with dementia. We evaluated the effects of physical and cognitive activity on learning and memory in a rat model of vascular dementia (VasD). Male Sprague-Dawley rats (6 months old) were exposed to either regular chow or a diet rich in saturated fats and sucrose and chronic bilateral common carotid artery occlusion or sham surgery. First, this model of VasD was validated using a 2 × 2 experimental design (surgery × diet) and standard cognitive outcomes. Next, using identical surgical procedures, we exposed animals to a paradigm of cognitive rehabilitation or a sedentary condition. At 16 weeks post surgery, VasD animals demonstrated significant learning and memory deficits in the Morris water maze, independent of diet. Rehabilitation significantly attenuated these cognitive deficits at this time point as well as at 24 weeks. Further, rehabilitation normalized hippocampal CA1 soma size (area and volume) to that of control animals, independent of cell number. Importantly, these findings demonstrate beneficial neuroplasticity in early middle-aged rats that promoted cognitive recovery, an area rarely explored in preclinical studies.

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.

Visualizing the Engram: Learning Stabilizes Odor Representations in the Olfactory Network

The nature of memory is a central issue in neuroscience. How does our representation of the world change with learning and experience? Here we use the transcription of Arc mRNA, which permits probing the neural representations of temporally separated events, to address this in a well characterized odor learning model. Rat pups readily associate odor with maternal care. In pups, the lateralized olfactory networks are independent, permitting separate training and within-subject control. We use multiday training to create an enduring memory of peppermint odor. Training stabilized rewarded, but not nonrewarded, odor representations in both mitral cells and associated granule cells of the olfactory bulb and in the pyramidal cells of the anterior piriform cortex. An enlarged core of stable, likely highly active neurons represent rewarded odor at both stages of the olfactory network. Odor representations in anterior piriform cortex were sparser than typical in adult rat and did not enlarge with learning. This sparser representation of odor is congruent with the maturation of lateral olfactory tract input in rat pups. Cortical representations elsewhere have been shown to be highly variable in electrophysiological experiments, suggesting brains operate normally using dynamic and network-modulated representations. The olfactory cortical representations here are consistent with the generalized associative model of sparse variable cortical representation, as normal responses to repeated odors were highly variable (∼70% of the cells change as indexed by Arc). Learning and memory modified rewarded odor ensembles to increase stability in a core representational component.

A Cognitive Rehabilitation Paradigm Effective in Male Rats Lacks Efficacy in Female Rats

Cognitive dysfunction, as a consequence of dementia, is a significant cause of morbidity lacking efficacious treatment. Females comprise at least half of this demographic but have been vastly underrepresented in preclinical studies. The current study addressed this gap by assessing the protective efficacy of physical exercise and cognitive activity on learning and memory outcomes in a rat model of vascular dementia. Forty ovariectomized Sprague-Dawley rats (~6 months old) were exposed to either a diet high in saturated fats and refined sugars or standard laboratory chow and underwent either chronic bilateral carotid occlusion or Sham surgery. Learning and memory abilities were evaluated using standard cognitive outcomes over the ensuing 6 months, followed by histologic analyses of hippocampal CA1 neurons. In Experiment 1, we confirmed hypoperfusion-induced cognitive dysfunction using a 2 × 2 (Surgery × Diet) experimental design, without alterations in hippocampal architecture. In Experiment 2, hypoperfused animals were either exposed to alternating days of physical (wheel running) and cognitive activity (modified Hebb–Williams maze) or sedentary housing. In contrast to males, this combination rehabilitation paradigm did not improve cognition or histopathologic outcomes in hypoperfused animals. These findings, highlighting differences between female and male animals, show the necessity of including both sexes in preclinical experimentation.

Low-protein diet increases sexual behaviour and response to electric shock in adult male rats

Adult male rats were maintained for 4 weeks on an 8% protein diet or a 22% protein diet. During the fifth week the two groups were assessed for sexual behavior, flinch and jump thresholds, and noise-elicited startle habituation. Rats on the low protein diet exhibited significantly more mounting with thrusts and were sensitive to lower levels of shock as indicated by flinch threshold differences. Low protein rats did not differ with respect to jump thresholds or startle response habituation. After a rehabilitation diet the differences in sexual behavior were no longer apparent.