Regulation Of Behavioral State Research Articles

Convergence of monosynaptic inputs from neurons in the brainstem and forebrain on parabrachial neurons that project to the paraventricular nucleus of the thalamus

The paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in regulating behavior. Homeostatic challenges and salient cues activate the PVT and evidence shows that the PVT regulates appetitive and aversive responses. The brainstem is a source of afferents to the PVT and the present study was done to determine if the lateral parabrachial nucleus (LPB) is a relay for inputs to the PVT. Retrograde tracing experiments with cholera toxin B (CTB) demonstrate that the LPB contains more PVT projecting neurons than other regions of the brainstem including the catecholamine cell groups. The hypothesis that the LPB is a relay for signals to the PVT was assessed using an intersectional monosynaptic rabies tracing approach. Sources of inputs to LPB included the reticular formation; periaqueductal gray (PAG); nucleus cuneiformis; and superior and inferior colliculi. Distinctive clusters of input cells to LPB-PVT projecting neurons were also found in the dorsolateral bed nucleus of the stria terminalis (BSTDL) and the lateral central nucleus of the amygdala (CeL). Anterograde viral tracing demonstrates that LPB-PVT neurons densely innervate all regions of the PVT in addition to providing collateral innervation to the preoptic area, lateral hypothalamus, zona incerta and PAG but not the BSTDL and CeL. The paper discusses the anatomical evidence that suggests that the PVT is part of a network of interconnected neurons involved in arousal, homeostasis, and the regulation of behavioral states with forebrain regions potentially providing descending modulation or gating of signals relayed from the LPB to the PVT.

Functional Dissection of Glutamatergic and GABAergic Neurons in the Bed Nucleus of the Stria Terminalis.

The bed nucleus of the stria terminalis (BNST)—a key part of the extended amygdala—has been implicated in the regulation of diverse behavioral states, ranging from anxiety and reward processing to feeding behavior. Among the host of distinct types of neurons within the BNST, recent investigations employing cell type- and projection-specific circuit dissection techniques (such as optogenetics, chemogenetics, deep-brain calcium imaging, and the genetic and viral methods for targeting specific types of cells) have highlighted the key roles of glutamatergic and GABAergic neurons and their axonal projections. As anticipated from their primary roles in excitatory and inhibitory neurotransmission, these studies established that the glutamatergic and GABAergic subpopulations of the BNST oppositely regulate diverse behavioral states. At the same time, these studies have also revealed unexpected functional specificity and heterogeneity within each subpopulation. In this Minireview, we introduce the body of studies that investigated the function of glutamatergic and GABAergic BNST neurons and their circuits. We also discuss unresolved questions and future directions for a more complete understanding of the cellular diversity and functional heterogeneity within the BNST.

The Role of the Central Histaminergic System in Behavioral State Control.

Histamine is a small monoamine signaling molecule that plays a role in many peripheral and central physiological processes, including the regulation of wakefulness. The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and histamine neurons are thought to promote wakefulness and vigilance maintenance - under certain environmental and/or behavioral contexts - through their diffuse innervation of the cortex and other wake-promoting brain circuits. Histamine neurons also contain a number of other putative neurotransmitters, although the functional role of these co-transmitters remains incompletely understood. Within the brain histamine operates through three receptor subtypes that are located on pre- and post-synaptic membranes. Some histamine receptors exhibit constitutive activity, and hence exist in an activated state even in the absence of histamine. Newer medications used to reduce sleepiness in narcolepsy patients in fact enhance histamine signaling by blunting the constitutive activity of these histamine receptors. In this chapter, we provide an overview of the central histamine system with an emphasis on its role in behavioral state regulation and how drugs targeting histamine receptors are used clinically to treat a wide range of sleep-wake disorders.

Multimodal Neurological Enhancement Intervention for Self-regulation in Premature Infants.

The neonatal intensive care unit is often a noisy, overstimulating environment that disrupts infants' regulation of physiological and behavioral states and interrupts caregiver bonding; however, infants benefit from early intervention, including the use of multimodal neurological enhancement (MMNE) intervention to provide appropriate neurodevelopmental stimulation. No one has investigated whether it assists infants in self-regulation. The purpose of this retrospective longitudinal analysis was to examine the effect of a music therapy intervention, MMNE, on self-regulation of premature infants as measured by changes in heart rate (HR). A convenience sample of 60 premature infants received 486 MMNE sessions provided by a board-certified music therapist (MT-BC). Documentation, taken during routine clinical services, involved recording infant's HRs from the standard monitor for 3 minutes at baseline, during, and after a 20-minute MMNE intervention. Infants' mean HRs were decreased during and post-MMNE sessions compared with baseline (P < .004 and P < .001, respectively). Furthermore, infants with a baseline HR above 170 had significant decreases both during and after the MMNE session (P < .001 for both time periods). Results of this study support the existing body of evidence showing the benefits of MMNE with premature infants. Based on our results, MMNE may help infants develop and demonstrate self-regulation as indicated by maintained HRs during and after the intervention as well as a lowered HR for infants who had high HRs prior to MMNE. Further research needs to be done regarding how infants process MMNE and its potential to aid sensory processing.

M4-muscarinic acetylcholine receptor into the pedunculopontine tegmental nucleus mediates respiratory modulation of conscious rats

The pedunculopontine tegmental nucleus (PPTg) has been shown to have important functions relevant to the regulation of behavioral states and various motor control systems, including breathing control. The PPTg is considered an important nucleus in the mesopontine region with considerably cholinergic input to the ventral respiratory column. In addition, recent studies indicate that cholinergic innervation of the ventral respiratory column may play an important role in modulation of breathing. Here, we investigated the cholinergic stimulation of the PPTg and the changes in breathing output in conscious rats. Male Wistar rats (280–350 g, N = 5–12/group) with unilateral stainless steel cannula implanted into the PPTg were used. Respiratory parameters (tidal volume (VT), respiratory frequency (fR) and ventilation (VE)) were analyzed by whole body plethysmography. In unrestrained awake rats, unilateral injection of the cholinergic muscarinic agonist carbachol (10 mM–100 nL) in the PPTg decreased fR, and increase VT, without changing VE. The changes in fR and VT elicited by carbachol into the PPTg are abolished by previous blockade of the M4 muscarinic cholinergic receptors tropicamide into the PPTg. No significant changes in fR and VT elicited by carbachol were observed after blockade of the M1 and/or M3 muscarinic cholinergic receptors pirenzepine or 4-DAMP into the PPTg. Our data suggest that the changes in fR and VT produced by muscarinic cholinergic stimulation of PPTg is presumably mediated through a Gi-coupled M4 muscarinic receptors.

Sexually Dimorphic Regulation of Behavioral States by Dopamine in Caenorhabditis elegans.

Sex differences in behavior allow animals to effectively mate and reproduce. However, the mechanism by which biological sex regulates behavioral states, which underlie the regulation of sex-shared behaviors, such as locomotion, is largely unknown. In this study, we studied sex differences in the behavioral states of Caenorhabditis elegans and found that males spend less time in a low locomotor activity state than hermaphrodites and that dopamine generates this sex difference. In males, dopamine reduces the low activity state by acting in the same pathway as polycystic kidney disease-related genes that function in male-specific neurons. In hermaphrodites, dopamine increases the low activity state by suppression of octopamine signaling in the sex-shared SIA neurons, which have reduced responsiveness to octopamine in males. Furthermore, dopamine promotes exploration both inside and outside of bacterial lawn (the food source) in males and suppresses it in hermaphrodites. These results demonstrate that sexually dimorphic signaling allows the same neuromodulator to promote adaptive behavior for each sex.SIGNIFICANCE STATEMENT The mechanisms that generate sex differences in sex-shared behaviors, including locomotion, are not well understood. We show that there are sex differences in the regulation of behavioral states in the model animal Caenorhabditis elegans Dopamine promotes the high locomotor activity state in males, which must search for mates to reproduce, and suppresses it in self-fertilizing hermaphrodites through distinct molecular mechanisms. This study demonstrates that sex-specific signaling generates sex differences in the regulation of behavioral states, which in turn modulates the locomotor activity to suit reproduction for each sex.

Intracerebroventricular injection of histamine induces the hypothalamic-pituitary-gonadal axis activation in male rats

Brain histamine holds a key position in the regulation of behavioral states, biological rhythms, body weight, energy metabolism, thermoregulation, fluid balance, stress and reproduction in female animals. However, it is not clear whether central histamine exerts any effect on hypothalamic-pituitary-testicular in male rats and if so, the involvement of type of central histamine receptors.The current study was designed to determine the effect of centrally administrated histamine on plasma gonadotropin hormone-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone level, and sperm parameters, and to show the mediation of the central histaminergic H1, H2 and H3/H4 receptors on histamine-evoked hormonal and sperm parameters’ effects.Studies were performed in male Sprague-Dawley rats. A total of 50 or 100 nmol doses of histamine were injected intracerebroventricularly (icv). 100 nmol dose of histamine significantly caused increases in plasma GnRH, LH, FSH and testosterone levels of animals, but not 50 nmol dose of histamine. Moreover, central pretreatment with chlorpheniramine, histaminergic H1 receptor antagonist (100 nmol), ranitidine and histaminergic H2 receptor antagonist (100 nmol) completely prevented histamine evoked increase in plasma GnRH, LH, FSH and testosterone levels, while thioperamide, histaminergic H3/H4 receptor antagonist (100 nmol) pretreatment failed to reverse sex hormones responses to histamine. Both central histamine treatment alone and central histamine treatment after central histaminergic receptors antagonists’ pretreatments did not alter any sperm parameters in rats.In conclusion, our findings show that centrally administered histamine increases plasma GnRH, LH, FSH and testosterone levels of conscious male rats without change any sperm parameters. Moreover, according to our findings, central histaminergic H1, and H2 receptors mediate these histamine-induced effects.

Transcription Factor E2F3a in Nucleus Accumbens Affects Cocaine Action via Transcription and Alternative Splicing

BackgroundLasting changes in gene expression in brain reward regions, including nucleus accumbens (NAc), contribute to persistent functional changes in the addicted brain. We and others have demonstrated that altered expression of several candidate transcription factors in NAc regulates drug responses. A recent large-scale genome-wide study from our group predicted transcription factor E2F3 (E2F3) as a prominent upstream regulator of cocaine-induced changes in gene expression and alternative splicing. MethodsWe studied expression of two E2F3 isoforms—E2F3a and E2F3b—in mouse NAc after repeated cocaine administration and assayed the effects of overexpression or depletion of E2f3 isoforms in NAc on cocaine behavioral responses. We then performed RNA sequencing to investigate the effect of E2f3a overexpression in this region on gene expression and alternative splicing and performed quantitative chromatin immunoprecipitation at downstream targets in NAc following E2f3a overexpression or repeated cocaine exposure. Sample sizes varied between experiments and are noted in the text. ResultsWe showed that E2f3a, but not E2f3b, overexpression or knockdown in mouse NAc regulates cocaine-induced locomotor and place conditioning behavior. Furthermore, we demonstrated that E2f3a overexpression substantially recapitulates genome-wide transcriptional profiles and alternative splicing induced by cocaine. We further validated direct binding of E2F3a at key target genes following cocaine exposure. ConclusionsThis study establishes E2F3a as a novel transcriptional regulator of cocaine action in NAc. The findings reveal a crucial role for E2F3a in the regulation of cocaine-elicited behavioral states. Moreover, the importance of this role is bolstered by the extensive recapitulation of cocaine’s transcriptional effects in NAc by overexpression of E2f3a.

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states.

Striatal Circuits as a Common Node for Autism Pathophysiology.

Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains—deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD.

β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory.

Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are “earmarked” for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories.

A Framework for Quantitative Modeling of Neural Circuits Involved in Sleep-to-Wake Transition.

Identifying the neuronal circuits and dynamics of sleep-to-wake transition is essential to understanding brain regulation of behavioral states, including sleep–wake cycles, arousal, and hyperarousal. Recent work by different laboratories has used optogenetics to determine the role of individual neuromodulators in state transitions. The optogenetically driven data do not yet provide a multi-dimensional schematic of the mechanisms underlying changes in vigilance states. This work presents a modeling framework to interpret, assist, and drive research on the sleep-regulatory network. We identify feedback, redundancy, and gating hierarchy as three fundamental aspects of this model. The presented model is expected to expand as additional data on the contribution of each transmitter to a vigilance state becomes available. Incorporation of conductance-based models of neuronal ensembles into this model and existing models of cortical excitability will provide more comprehensive insight into sleep dynamics as well as sleep and arousal-related disorders.

The Effects of Orexin A and B on Two Forms of Immobility Responses and on Analgesia

The orexins are important for the regulation of several behavioral patterns, including feeding, arousal state, drug seeking, voluntary locomotion and nociception. Two orexins (A and B), and two different orexin receptors are known, which have differential distribution. This suggests that orexins and distinct orexin receptors may regulate specific behaviors such as immobility associated analgesia. The periaqueductal gray (PAG) is considered to be the main center for the analgesia and immobility responses in the central nervous system (CNS). Here we compared the effect of orexin A (OX-A) and orexin B (OX-B) after intracerebroventricular (ICV) or the ventrolateral periaqueductal gray (vl-PAG) injection. Two forms of immobility responses were studied: cataleptic (CAT) and tonic (TI) responses. The latter was associated with analgesia as part of a defensive response in several species. We observed that OX-A was more effective than OX-B to reduce CAT; OX-B was slightly more potent than OX-A to decrease TI and neither orexins were able to induce analgesia when orexins were injected ICV. After microinjection into vl-PAG CAT was unaffected by orexins and both orexins significantly decrease TI. Microinjected OX-A did not show analgesic activity but OX-B produced significant analgesic effect assessed by tail-flick test.

Brain Volume and Neurobehavior in Newborns with Complex Congenital Heart Defects

To investigate the relationship between tissue-specific alterations in brain volume and neurobehavioral status in newborns with complex congenital heart defects preoperatively. Three-dimensional volumetric magnetic resonance imaging was used to calculate tissue-specific brain volumes and a standardized neurobehavioral assessment was performed to assess neurobehavioral status in 35 full-term newborns admitted to the hospital before cardiopulmonary bypass surgery. Multiple linear regression models were performed to evaluate relationships between neurobehavioral status and brain volumes. Reduced subcortical gray matter (SCGM) volume and increased cerebrospinal fluid (CSF) volume were associated with poor behavioral state regulation (SCGM, P = .04; CSF, P = .007) and poor visual orienting (CSF, P = .003). In cyanotic newborns, reduced SCGM was associated with higher overall abnormal scores on the assessment (P = .001) and poor behavioral state regulation (P = .04), and increased CSF volume was associated with poor behavioral state regulation (P = .02), and poor visual orienting (P = .02). Conversely, acyanotic newborns showed associations between reduced cerebellar volume and poor behavioral state regulation (P = .03). Abnormal neurobehavior is associated with impaired volumetric brain growth before open heart surgery in infants with complex congenital heart defects. This study highlights a need for routine preoperative screening and early intervention to improve neurodevelopmental outcomes.

Measures of infant behavioral and physiological state regulation predict 54-month behavior problems.

This study investigated whether measures of infant temperament, regulatory disorders, and physiological reactivity and concurrent measures of family environment were predictors of child behavior problems at 54 months of age. The sample consisted of 23 children-mother dyads. The sample recruitment strategy emphasized testing both typical and fussy/difficult infants at 9 months of age. Children were categorized into low and high behavioral problem groups at 54 months of age. The children in the high behavioral problem group were more likely at 9 months to have been temperamentally difficult, to have been classified as regulatory disordered, and to have displayed respiratory sinus arrhythmia (RSA) regulation difficulties. These children also were more likely to come from families described as less cohesive and providing less focus on active/recreational activities when the children were 54 months old. A logistic regression analysis, including only the 9-month infant measures (i.e., difficultness, regulatory disorders classification, and RSA regulation), resulted in a significant model with 100.0% accurate classification into high or low behavioral problem groups. Data suggest that infant measures of behavioral and physiological state regulation may be early indicators of child behavior problems, especially internalizing problems.

Different Inner Retinal Pathways Mediate Rod-Cone Input in Irradiance Detection for the Pupillary Light Reflex and Regulation of Behavioral State in Mice

Detection of light in the eye contributes both to spatial awareness (form vision) and to responses that acclimate an animal to gross changes in light (irradiance detection). This dual role means that eye disease that disrupts form vision can also adversely affect physiology and behavioral state. The purpose of this study was to investigate how inner retinal circuitry mediating rod-cone photoreceptor input contributes to functionally distinct irradiance responses and whether that might account for phenotypic diversity in retinal disease. The sensitivity of the pupillary light reflex and negative masking (activity suppression by light) was measured in wild-type mice with intact inner retinal circuitry, Nob4 mice that lack ON-bipolar cell function, and rd1 mice that lack rods and cones and, therefore, have no input to ON or OFF bipolar cells. An expected increase in sensitivity to negative masking with loss of photoreceptor input in rd1 was duplicated in Nob4 mice. In contrast, sensitivity of the pupillary light reflex was more severely reduced in rd1 than in Nob4 mice. Absence of ON-bipolar cell-mediated rod-cone input can fully explain the phenotype of outer retina degeneration for negative masking but not for the pupillary light reflex. Therefore, inner retinal pathways mediating rod-cone input are different for negative masking and the pupillary light reflex.

Temperament and Sleep-Wake Behaviors from Infancy to Toddlerhood.

Sleep-wake behaviors and temperament were examined longitudinally for trait stability and relationship to behavioral state regulation from infancy to early childhood. Subjects were 120 low-risk, full-term infants from a middle class sample. At 6 weeks, parents completed 3 consecutive days of the Baby's Day Diary which measures sleep, wake, fuss, feed and cry states and the Infant Characteristics Questionnaire. At 16 months, parents assessed sleep behaviors with the Sleep Habits Inventory and temperament with the Toddler Symptom Checklist. At 24 months, parents repeated 3 days of the Baby's Day Diary. Structural Equation Modeling was used to examine cross-age hypotheses for sleep-wake and temperament associations. From early infancy to toddlerhood, sleep-wake behaviors and irritable temperament were notably stable but independent in this cohort.

GABAergic actions on cholinergic laterodorsal tegmental neurons: implications for control of behavioral state

Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) play a critical role in regulation of behavioral state. Therefore, elucidation of mechanisms that control their activity is vital for understanding of how switching between wakefulness, sleep and anesthetic states is effectuated. In vivo studies suggest that GABAergic mechanisms within the pons play a critical role in behavioral state switching. However, the postsynaptic, electrophysiological actions of GABA on LDT neurons, as well as the identity of GABA receptors present in the LDT mediating these actions is virtually unexplored. Therefore, we studied the actions of GABA agonists and antagonists on cholinergic LDT cells by performing patch clamp recordings in mouse brain slices. Under conditions where detection of Cl − -mediated events was optimized, GABA induced gabazine (GZ)-sensitive inward currents in the majority of LDT neurons. Post-synaptic location of GABA A receptors was demonstrated by persistence of muscimol-induced inward currents in TTX and low Ca 2+ solutions. THIP, a selective GABA A receptor agonist with a preference for δ-subunit containing GABA A receptors, induced inward currents, suggesting the existence of extrasynaptic GABA A receptors. LDT cells also possess GABA B receptors as baclofen-activated a TTX- and low Ca 2+-resistant outward current that was attenuated by the GABA B antagonists CGP 55845 and saclofen. The tertiapin sensitivity of baclofen-induced outward currents suggests that a G IRK mediated this effect. Further, outward currents were never additive with those induced by application of carbachol, suggesting that they were mediated by activation of GABA B receptors linked to the same G IRK activated in these cells by muscarinic receptor stimulation. Activation of GABA B receptors inhibited Ca 2+ increases induced by a depolarizing voltage step shown previously to activate VOCCs in cholinergic LDT neurons. Baclofen-mediated reductions in depolarization-induced Ca 2+ were unaltered by prior emptying of intracellular Ca 2+ stores, but were abolished by low extracellular Ca 2+ and pre-application of nifedipine, indicating that activation of GABA B receptors inhibits influx of Ca 2+ involving L-type Ca 2+ channels. Presence of GABA C receptors is suggested by the induction of inward current by (E)-4- amino-2-butenoic acid (TACA) and its inhibition by 1,2,5,6-tetrahydropyridine-4-ylmethylphosphinic (TPMPA), a relatively selective agonist and antagonist, respectively, of GABA C receptors. All of these GABA-mediated actions were found to occur in histochemically-identified cholinergic neurons. Taken together, these data indicate for the first time that cholinergic neurons of the LDT exhibit functional GABA A, B and C receptors, including extrasynaptically located GABA A receptors, which may be tonically activated by synaptic overflow of GABA. Accordingly, the activity of cholinergic LDT neurons is likely to be significantly affected by GABAergic tone within the nucleus, and so, demonstrated effects of GABA on behavioral state may be mediated, in part, via direct actions on cholinergic neurons in the LDT.

Behavioral State Regulation of Dendrodendritic Synaptic Inhibition in the Olfactory Bulb

Behavioral states regulate how information is processed in local neuronal circuits. Here, we asked whether dendrodendritic synaptic interactions in the olfactory bulb vary with brain and behavioral states. To examine the state-dependent change of the dendrodendritic synaptic transmission, we monitored changes in field potential responses in the olfactory bulb of urethane-anesthetized and freely behaving rats. In urethane-anesthetized rats, granule-to-mitral dendrodendritic synaptic inhibition was larger and longer when slow waves were present in the electroencephalogram (slow-wave state) than during the fast-wave state. The state-dependent alternating change in the granule-to-mitral inhibition was regulated by the cholinergic system. In addition, the frequency of the spontaneous oscillatory activity of local field potentials and periodic discharges of mitral cells in the olfactory bulb shifted in synchrony with shifts in the neocortical brain state. Freely behaving rats showed multilevel changes in dendrodendritic synaptic inhibition that corresponded to diverse behavioral states; the inhibition was the largest during slow-wave sleep state, and successively smaller during light sleep, awake immobility, and awake moving states. These results provide evidence that behavioral state-dependent global changes in cholinergic tone modulate dendrodendritic synaptic inhibition and the information processing mode in the olfactory bulb.

Intense exercise increases adenosine concentrations in rat brain: Implications for a homeostatic sleep drive

Intense exercise and sleep deprivation affect the amount of homeostatically regulated slow wave sleep in the subsequent sleep period. Since brain energy metabolism plays a decisive role in the regulation of behavioral states, we determined the concentrations of nucleotides and nucleosides: phosphocreatine, creatine, ATP, ADP, AMP, adenosine, and inosine after moderate and exhaustive treadmill exercise as well as 3 and 5 h of sleep deprivation and sleep in the rat brain using the freeze-clamp technique. High intensity exercise resulted in a significant increase of the sleep-promoting substance adenosine. In contrast, following sleep, inosine and adenosine levels declined considerably, with an accompanied increase of ADP after 3 h and ATP after 5 h. Following 3 h and 5 h sleep deprivation, ADP and ATP did not differ significantly, whereas inosine increased during the 3 and 5-h period. The concentrations of AMP, creatine and phosphocreatine remained unchanged between experimental conditions. The present results are in agreement with findings from other authors and suggest that depletion of cerebral energy stores and accumulation of the sleep promoting substance adenosine after high intensity exercise may play a key role in homeostatic sleep regulation, and that sleep may play an essential role in replenishment of high-energy compounds.