Hippocampal Noradrenaline Regulates Spatial Working Memory in the Rat

Gulino, Rosario; Kostenko, Anna; Leo, Gioacchino de; Emmi, Serena Alexa; Nunziata, Domenico; Leanza, Giampiero

doi:10.1016/b978-0-12-805088-0.00010-4

Cited by 4 publications

(14 citation statements)

References 52 publications

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“…These data appear to confirm and extend previous findings of NA-related effects on spatial navigation induced by aging, 73 , 74 pharmacological manipulations, 75 , 76 non-selective neurotoxin 77 , 78 or—more recently—selective immunotoxin lesions. 49 , 50 , 79 Notably, the working memory deficits detected here in animals with neonatal intraventricular administration of αDBH-saporin (see also Pintus et al . 49 ) are very similar in magnitude to those reported previously following discrete intrahippocampal injections of the same immunotoxin.…”

Section: Discussionmentioning

confidence: 52%

“… 49 ) are very similar in magnitude to those reported previously following discrete intrahippocampal injections of the same immunotoxin. 79 This is of importance, as it would strongly suggest that—at least in the rat and with the experimental paradigm adopted here—the NA-mediated events critical for the normal execution of a working memory task may take place also at the level of the hippocampus. Moreover, the time course of those investigations (≈8–12 months) supports the notion of a high stability over time of the anatomical and functional effects induced the neonatal lesioning treatment.…”

Section: Discussionmentioning

confidence: 82%

“…Interestingly, however, we have previously shown that reference or working memory functions, severely perturbed even many months following selective cholinergic or noradrenergic lesions, can be ameliorated/normalized by transplanted cholinergic 55 , 91 or noradrenergic 49 , 79 neural precursors promoting reinnervation of the depleted hippocampal target regions. These restorative actions apply as well to the lesion-induced pathological transformation of resident peptides or proteins, 49 , 55 but presently there are no data substantiating similar effects on tissue pathology possibly triggered by a concurrent cholinergic–noradrenergic loss.…”

Section: Discussionmentioning

confidence: 99%

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Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory

Leo

Gulino

Coradazzi

et al. 2022

Brain Communications

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Severe loss of cholinergic neurons in the basal forebrain nuclei and of noradrenergic neurons in the locus coeruleus are almost invariant histopathological hallmarks of Alzheimer’s disease. However, the role of these transmitter systems in the spectrum of cognitive dysfunctions typical of the disease is still unclear, nor is it yet fully known whether do these systems interact and how. Selective ablation of either neuronal population, or both of them combined, were produced in developing animals to investigate their respective and/or concurrent contribution to spatial learning and memory, known to be severely affected in Alzheimer’s disease. Single or double lesions were created in 4-8 days old rats by bilateral intraventricular infusion of two selective immunotoxins. At about 16 weeks of age, the animals underwent behavioral tests specifically designed to evaluate reference and working memory abilities, and their brains were later processed for quantitative morphological analyses. Animals with lesion to either system alone showed no significant reference memory deficits which, by contrast, were evident in the double-lesioned subjects. These animals could not adopt an efficient search strategy on a given testing day and were unable to transfer all relevant information to the next day, suggesting deficits in acquisition, storage and/or recall. Only animals with single noradrenergic or double lesions exhibited impaired working memory. Interestingly, ablation of cholinergic afferents to the hippocampus stimulated a robust ingrowth of thick fibers from the superior cervical ganglion which, however, did not appear to have contributed to the observed cognitive performance. Ascending cholinergic and noradrenergic afferents to the hippocampus and neocortex appear to be primarily involved in the regulation of different cognitive domains, but they may functionally interact, mainly at hippocampal level, for sustaining normal learning and memory. Moreover, these transmitter systems are likely to compensate for each other, but apparently not via ingrowing sympathetic fibers.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory

Leo

Gulino

Coradazzi

et al. 2022

Brain Communications

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“…Indeed, during normal aging up to 25% of LC neurons, responsible for ~50% of brain NA levels, are lost in the elderly (>90 years age) [ 51 ]. Therefore several strategies have been proposed to prevent neurodegeneration by astrocytic adrenergic activation [ 73 ] including the (i) exposure of the subjects to enriched sensory environment or to electrical stimulation, even by deep brain stimulation [ 74 ]; (ii) transplanting noradrenergic neurons [ 66 , 75 ]; and (iii) applying drugs that elevate or normalize NA [ 76 ] and/or agonists acting in a similar manner as those on ARs, although via different receptors. It is the latter strategy that may be employed to mimic the action of NA under conditions when NA levels are reduced due to the age- and or disease-related demise of LC neurons.…”

Section: Adrenergic Regulation Of Astrocytic Glycolysis and Metabomentioning

confidence: 99%

Metabolic Plasticity of Astrocytes and Aging of the Brain

Morita

Ikeshima-Kataoka

Kreft

et al. 2019

IJMS

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As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions.

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“…Thus, it appears highly plausible that the influence exerted by LC-derived noradrenergic inputs to regulate the complex series of events leading to the proliferation of newly generated progenitors in the SGZ may also involve the regulation of distinct aspects of cognitive function (i.e., working memory). Interestingly, reinstating hippocampal noradrenergic neurotransmission using, e.g., locally implanted noradrenergic neuroblasts, has recently been observed to promote a significant amelioration of working memory performance disrupted by the lesion [ 24 , 25 ]. However, no study to date has addressed whether such transplant-promoted recovery of working memory abilities would also affect the proliferation of precursor cells in the hippocampal SGZ.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Noradrenaline Is a Positive Regulator of Spatial Working Memory and Neurogenesis in the Rat

Gulino

Nunziata

Leo

et al. 2023

IJMS

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Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62–65% reduction in proliferating 5-bromo-2′deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus.

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Hippocampal Noradrenaline Regulates Spatial Working Memory in the Rat

Cited by 4 publications

References 52 publications

Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory

Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory

Metabolic Plasticity of Astrocytes and Aging of the Brain

Hippocampal Noradrenaline Is a Positive Regulator of Spatial Working Memory and Neurogenesis in the Rat

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