Neurodegenerative diseases constitute a heterogeneous group of age-related disorders that are characterized by a slow but irreversible deterioration of brain functions. Evidence accumulated over more than two decades has implicated calcium-related homeostatic mechanisms, giving rise to the Ca2+ hypothesis of brain aging and, ultimately, cell death. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter within the central (CNS), peripheral and enteric nervous systems. It appears to be involved in a wide variety of physiological functions within and outside the nervous system, that are maintained through a complex interaction between GABA and calcium-dependent neurotransmission and cellular metabolic functions. Within CNS the Ca2+/GABA mechanism stabilizes neuronal activity both at cellular and systemic levels. Decline in the Ca2 +/GABA control initiates several cascading processes leading to both weakened protective barriers (in particular the blood-brain barrier) and accumulations of intracellular deposits of calcium and Lewy bodies. Linking such a vital mechanism of synaptic transmission with metabolism (both at cellular and tissue level) by means of a common reciprocal Ca2+/GABA inhibition results in a fragile balance, which is prone to destabilization and auto-destruction. The GABA decline etiology proposed here appears to apply to all human neurodegenerative processes initiated by abnormal intracellular calcium levels. Therefore, the original description of Parkinson’s disease (PD) as due to the selective damage of dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder of the nervous system, whose clinical symptoms reflect the localization and progression of the most advanced GABA pathology. A future and more complete therapeutic approach to PD should be aimed first at slowing (or stopping) the progression of Ca2+/GABA functional decline.

There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production—which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons. This review summarizes the complex interrelationships between metabolic processes on the systemic and cellular levels and provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.

Emotional states displayed by an animal or a human can seriously affect behavior of their conspecifics. The amygdala plays a crucial role in the processing of emotions. In this study, we describe an experimental rat model of between-subject transfer of emotional information and its effects on activation of the amygdala. The rats were kept in pairs, and one animal (designated as “demonstrator”) was treated to specific behavioral training of either foot-shock-reinforced context conditioning or just exposure to a novel context. We next examined the influence of the demonstrators on the exploratory behavior of their cagemates (called “observers”) and the observers’ performance of the acoustic startle response. We report that we can distinguish both groups of observers from the control animals (as shown by startle-response measure) and distinguish between observers (by means of indexing the exploration), with respect to whether they were paired with demonstrators treated to different experimental conditions. Furthermore, we show that the observers have most of their amygdala activated (as revealed by c-Fos mapping) to the same level as the demonstrators and, in the case of the central amygdala, to an even higher level. Moreover, the level of c-Fos expression in the observers reflected the specific behavioral treatment of the demonstrators with whom they were paired. Thus, in this study, we have shown that undefined emotional information transferred by a cohabitant rat can be evaluated and measured and that it evokes very strong and information-specific activation of the amygdala.