Using two-sensor electrochemical recordings in freely moving rats, we examined the relationship between physiological and drug-induced oxygen fluctuations in the brain and periphery. Animals chronically implanted with oxygen sensors in the nucleus accumbens (NAc) and subcutaneous (SC) space were subjected to several mildly arousing stimuli (sound, tail-pinch and social interaction) and intravenous injections of cocaine and heroin. Arousing stimuli induced rapid increases in NAc oxygen levels followed by and correlated with oxygen decreases in the SC space. Therefore, cerebral vasodilation that increases cerebral blood flow and oxygen entry into brain tissue results from both direct neuronal activation and peripheral vasoconstriction, which redistributes arterial blood from periphery to the brain. The latter factor could also explain a similar pattern of oxygen responses found in the substantia nigra reticulata, suggesting hyperoxia as a global phenomenon with minor structural differences during early time intervals following the stimulus onset. While arousing stimuli and cocaine induced similar oxygen responses in the brain and SC space, heroin induced a biphasic down-up brain oxygen fluctuation associated with a monophasic oxygen decrease in the SC space. Oxygen decreases occurred more rapidly and stronger in the SC space, reflecting a drop in blood oxygen levels due to respiratory depression.
Spreading depression is characterized by slow, propagating wave of cellular depolarization (SD) and is wildly associated with migraine, stroke, and traumatic brain injury. Seizures and spreading depression (or spreading depolarization, SD) have long been reported to coincide in acute seizure induction experiments. However, SD has not been observed associated with spotaneous seizures in animal or clinical recordings. Recently, advances in acquisition systems for neurointensive care units have made routine observations of SD possible. In clinical epilepsy, SD has been suggested as a candidate mechanism for migraine/headache like events following seizures as well as for post-ictal generalized suppression. In animal models of epilepsy, seizure-induced brainstem SD has also been demonstrated as a mechanism of sudden unexplained death in epilepsy (SUDEP). The interplay between seizures and SD has also been suggested in computational models, where the two are components of the repetoir of neuronal activity.However, the spatiotemporal dynamics of SD with respect to spontaneous seizures in chronically epileptic brain remains ambigous. We analyzed continuous long-term DC sensitive EEG measurements from two fundamentally different animal models of chronic epilepsy. We found that SD was associated with approximately one-third of all spontaneous seizures in each model. Additionally, SDs participated in the organization of seizure clusters. These findings demonstrate that the underlying dynamic of epileptic events is broader than seizures alone.Significance StatementSpreading depression is characterized by slow, propagating wave of cellular spreading depolarization (SD) and is wildly associated with migraine, stroke, and traumatic brain injury. Although recently the linkage between SD and induced seizures has been recognized, the mechanistic relationship between SD and spontaneous seizures remains poorly understood. Here, we utilized long-term, stable, near-DC measurements of the brain activity in two fundamentally different animal models of epilepsy to investigate the SD-seizure interplay. We found that SD is a frequent phenomenon in the epileptic brain, in these models is associated with more than a third of all seizures, and appears to connect seizures in seizure clusters. Although in one model SD stereotypically propagates out from a single focus in the hippocampus, depression of the field-potentials is observed synchronously across much of the hippocampus. These observations highlight the value of stable DC measurements for accurate understanding of SD and its propagation. We found that spontaneous ictal events that include both seizures and SD are frequent in animal models of epilepsy. These findings suggest that SD could be a valuable target for treatment and control of epilepsy.
Sleep-wake regulation is thought to be governed by interactions among several nuclei in midbrain, pons, and hypothalamic regions. Determination of the causal role of these nuclei in state transitions requires simultaneous measurements from the nuclei with sufficient spatial and temporal resolution. We obtained long-term experimental single- and multi-unit measurements simultaneously from multiple nuclei of the putative hypothalamic and brainstem sleep-wake regulatory network in freely behaving rats. Cortical and hippocampal activity, along with head acceleration were also acquired to assess behavioral state. We found that although the average activity of cell groups during states matches the patterns presented previously in brief recordings of individual nuclei in head-fixed animals, the firing rates with respect to cortical and behavioral signs of state transitions differ in critical ways. Our findings pose fundamental questions about the neural mechanisms that maintain specific states and the neural interactions that lead to the emergence of new states.
Proper inflow of oxygen into brain tissue is essential for maintaining normal neural functions. Although oxygen levels in the brain's extracellular space depend upon a balance between its delivery from arterial blood and its metabolic consumption, the use of high-speed electrochemical detection revealed rapid increases in brain oxygen levels elicited by various salient sensory stimuli. These stimuli also increase intra-brain heat production, an index of metabolic neural activation, but these changes are slower and more prolonged than changes in oxygen levels. Therefore, under physiological conditions, the oxygen inflow into brain tissue exceeds its loss due to consumption, thus preventing any metabolic deficit. Here, we used oxygen sensors coupled with amperometry to examine the pattern of real-time oxygen fluctuations in the nucleus accumbens during glucose drinking behavior in trained rats. Following the exposure to a glucose-containing cup, oxygen levels rapidly increased, peaked when the rat initiated drinking, and relatively decreased during consumption. Similar oxygen changes but more episodic drinking occurred when Stevia, a calorie-free sweet substance, was substituted for glucose. When water was substituted for glucose, rats tested the water but refused to consume all of it. While the basic pattern of oxygen changes during this water test was similar to that with glucose drinking, the increases were larger. Finally, oxygen increases were significantly larger when rats were exposed to concealed glucose and made multiple unsuccessful attempts to obtain and consume it. Based on these data we discuss the mechanisms underlying behavior-related brain oxygen fluctuations and their functional significance.
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