Behavioral Characteristics of an Extremely Old Rhesus Macaque in a Zoo: Dementia-Like Symptoms and Implications for Quality of Life of Geriatric Animals.

Astrocytes are the most abundant glial cells in the brain, at least equaling or exceeding neurons in number []. They are highly branched and interact with many cell types, including neurons, other glial cells, and blood vessels []. Elaborate intracellular Ca signaling is a major characteristic of astrocytes, allowing them to communicate with adjacent cells. The subsequent release of gliotransmitters following the elevated Ca concentration plays critical roles in modulating synaptic transmission, synaptic plasticity, and brain blood flow [–]. However, circuit mechanisms mediating astrocytic Ca fluctuations and how gliotransmission contributes to the modulation of emotion and behaviors remain largely unknown [, ]. Based on the subcellular area, astrocytic Ca signals can be divided into global Ca fluctuations occurring in the soma and dynamic Ca changes spatially restricted to the fine processes, termed Ca microdomains. Different from the soma, astrocyte processes generate Ca fluctuations randomly [], and the events occur much more frequently than in the soma [–]. The astrocytic Ca signals can be attributed by either extracellular Ca influx or inositol triphosphate type 2 receptor (IPR2)-mediated store Ca release []. However, whether and how these two types of Ca sources contribute differentially to gliotransmission in different sub-cellular regions remains unclear. The physiological importance of astrocytic Ca fluctuations in the soma and processes remains poorly understood. Astrocytic Ca fluctuations have been shown to occur in response to a wide array of neurotransmitters including norepinephrine (NE) and dopamine (DA). The Ca signals of astrocytes are increased by electrical stimulation of the locus coeruleus (LC) in awake mice and this response is occluded by NE receptor inhibitors [, ], suggesting a role of LC neurons in the regulation of astrocytes. LC neurons provide abundant projections to the prefrontal cortex (PFC), where they release NE diffusely from axonal varicosities [] and regulate brain functions including arousal, attention, and memory. Importantly, LC neurons are one of the primary targets of cocaine and are closely associated with cocaine stimulant and relapse behaviors [–]. We have developed a micro carbon fiber-based electrochemical recording electrode ProCFE and recorded the first NE quantum release events from mammalian adrenal chromaffin cells and LC slices in situ, with which we strikingly found that, in addition to blocking the reuptake of NE, cocaine also plays critical roles in facilitating the quantal NE secretion NE transporter (NET)-dependent protein kinase C activation in LC neurons [–]. However, whether and how the increased NE release contributes to cocaine-related compulsive behaviors remains largely unknown.