Differential aging of the brain: Patterns, cognitive correlates and modifiers

Rats and mice have a tendency to interact more with a novel object than with a familiar object. This tendency has been used by behavioral pharmacologists and neuroscientists to study learning and memory. A popular protocol for such research is the object-recognition task. Animals are first placed in an apparatus and allowed to explore an object. After a prescribed interval, the animal is returned to the apparatus, which now contains the familiar object and a novel object. Object recognition is distinguished by more time spent interacting with the novel object. Although the exact processes that underlie this 'recognition memory' requires further elucidation, this method has been used to study mutant mice, aging deficits, early developmental influences, nootropic manipulations, teratological drug exposure and novelty seeking.

Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'

beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.

Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives

Mechanisms of Neuronal Degeneration in Alzheimer's Disease

Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Active solely during waking, they maintain wakefulness and attention. Three of the four known histamine receptors and binding to glutamate NMDA receptors serve multiple functions in the brain, particularly control of excitability and plasticity. H1 and H2 receptor-mediated actions are mostly excitatory; H3 receptors act as inhibitory auto- and heteroreceptors. Mutual interactions with other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, learning, and memory in health and disease.

Histamine in the Nervous System

1. The effects of histamine and agents at histamine receptors on spontaneous and 100 mM K(+)-evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving, rats, and on cognitive tests are described. 2. Local administration of histamine (0.1-100 microM) failed to affect spontaneous but inhibited 100 mM K(+)-stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)-alpha-methylhistamine (RAMH) (0.1-10 microM), imetit (0.01-10 microM) and immepip (0.01-10 microM) mimicked the effect of histamine. 3. Neither 2-thiazolylethylamine (TEA), an agonist showing some selectivity for H1 receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K(+)-evoked release of acetylcholine. 4. The inhibitory effect of 100 microM histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H1 and H2 but not H3 receptors. 5. The H3 receptor-induced inhibition of K(+)-evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX). 6. The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg-1) and RAMH (5 mg kg-1) were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K(+)-evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response. 7. These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

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Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats

The acquisition of active (shuttle-box) and passive avoidance conditioned responses and the effects of scopolamine on acetylcholine (ACh) output in freely moving rats and on conditioned responses were investigated 20 days after placing a unilateral lesion in the magnocellular forebrain nuclei (MFN) In the lesioned rats spontaneous ACh output from the cerebral cortex ipsilateral to the lesion was slightly decreased, while on the other hand the increase in ACh output elicited by scopolamine was strongly reduced Sham operated rats always performed more active avoidance responses than MFN lesioned rats in the daily training shuttle-box sessions, and the facilitating effect of scopolamine (1 mg/kg IP) on the shuttle-box performance was suppressed However the lesion did not disrupt the shuttle-box performance whenever training had taken place before the lesion In the lesioned rats retested 30 min after the training trial, an impairment of the passive avoidance response was found The effect of the lesion was potentiated by scopolamine The results show therefore that MFN lesions impair the cortical cholinergic mechanisms, whose activity seems to play an important role in cognitive functions

Lesions of cholinergic forebrain nuclei: changes in avoidance behavior and scopolamine actions.

Object recognition was investigated in adult and aging male rats in a two-trials, unrewarded, test that assessed a form of working-episodic memory. Exploration time in the first trial, in which two copies of the same object were presented, was recorded. In the second trial, in which one of the familiar objects and a new object were presented, the time spent exploring the two objects was separately recorded and a discrimination index was calculated. Adult rats explored the new object longer than the familiar object when the intertrial time ranged from 1 to 60 min. Rats older than 20 months of age did not discriminate between familiar and new objects. Object discrimination was lost in adult rats after scopolamine (0.2 mg/kg SC) administration and with lesions of the nucleus basalis, resulting in a 40% decrease in cortical ChAT activity. Both aniracetam (25, 50, 100 mg/kg os) and oxiracetam (50 mg/kg os) restored object recognition in aging rats, in rats treated with scopolamine, and with lesions of the nucleus basalis. In the rat, object discrimination appears to depend on the integrity of the cholinergic system, and nootropic drugs can correct its disruption.

L. Bartolini

Papers

Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats

Lesions of cholinergic forebrain nuclei: changes in avoidance behavior and scopolamine actions.

Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions.

Differential effects of amyloid peptides β-(1-40) and β-(25-35) injections into the rat nucleus basalis

Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models