Acetylcholine neuromodulation in normal and abnormal learning and memory: vigilance control in waking, sleep, autism, amnesia, and Alzheimer's disease

This article provides a unified mechanistic neural explanation of how learning, recognition, and cognition break down during Alzheimer's disease, medial temporal amnesia, and autism. It also clarifies whey there are often sleep disturbances during these disorders. A key mechanism is how acetylcholine modules vigilance control in cortical layer

A mathematical model of sleep-wake cycles: the role of hypocretin/orexin in homeostatic regulation and thalamic synchronization

Sleep is vital to our health and well-being. Yet, we do not have answers to such fundamental questions as “why do we sleep?” and “what are the mechanisms of sleep regulation?”. Better understanding of these issues can open new perspectives not only in basic neurophysiology but also in different pathological conditions that are going along with sleep disorders and/or disturbances of sleep, e.g. in mental or neurological diseases. A generally accepted concept that explains regulation of sleep was proposed in 1982 by Alexander Borb´ely. It postulates that sleep-wake transitions result from the interaction between a circadian and a homeostatic sleep processes. The circadian process is ascribed to a “genetic clock” in the neurons of the suprachiasmatic nucleus of the hypothalamus. The mechanisms of the homeostatic process are still unclear. In this study a novel concept of hypocretin (orexin) - based control of sleep homeostasis is presented. The neuropeptide hypocretin is a synaptic co-transmitter of neurons in the lateral hypothalamus. It was discovered in 1998 independently by two different groups, therefore, obtaining two names, hypocretin and orexin. This neuropeptide is required to maintain wakefulness. Dysfunction in the hypocretin system leads to the sleep disorder narcolepsy, which, among other symptoms, is characterized by severe disturbances of sleep-wake cycles with sudden sleep-attacks in the wake period and interruptions of the sleep phase. On the other hand injection of hypocretin promotes wakefulness and improves the performance of sleep deprived subjects. The major proposals of the present study are the following: 1) the homeostatic regulation of sleep depends on the dynamics of a neuropeptide hypocretin; 2) ongoing impulse generation of the hypocretin neurons during wakefulness is sustained by reciprocal excitatory connections with other neurons, including local glutamate interneurons; 3) the transition to a silent state (sleep) is going along with an activity-dependent weakening of the hypocretin synaptic efficacy; 4) during the silent state (sleep) synaptic efficacy recovers and firing (wakefulness) can be reinstalled due to the circadian or other input. This concept is realized in a mathematical model of sleep-wake cycles which is built up on a physiology-based, although simplified Hodgkin-Huxley-type approach. In the proposed model a hypocretin neuron is reciprocally connected with a local interneuron via excitatory glutamate synapses. The hypocretin neuron additionally releases the neuropeptide hypocretin as co-transmitter. Besides of the local glutamate interneurons hypocretin neuron excites two gap junction coupled thalamic neurons. The functionally relevant changes are introduced via activity-dependent alterations of the synaptic efficacy of hypocretin. It is decreasing with each action potential generated by the hypocretin neuron. This effect is superimposed by a slow, continuous recovery process. The decreasing synaptic efficacy during the active wake state introduces an increasing sleep pressure. Ist dissipation during the silent sleep state results from the synaptic recovery. The model data demonstrate that the proposed mechanisms can account for typical alterations of homeostatic changes in sleep and wake states, including the effects of an alarm clock, napping and sleep deprivation. In combination with a circadian input, the model mimics the experimentally demonstrated transitions between different activity states of hypothalamic and thalamic neurons. In agreement with sleep-wake cycles, the activity of hypothalamic neurons changes from silence to firing, and the activity of thalamic neurons changes from synchronized bursting to unsynchronized single-spike discharges. These simulation results support the proposed concept of state-dependent alterations of hypocretin effects as an important homeostatic process in sleep-wake regulation, although additional mechanisms may be involved

In vitro neuronal cultures on MEA: an engineering approach to study physiological and pathological brain networks

Reti neuronali accoppiate a matrici di microelettrodi: un metodo ingegneristico per studiare reti cerebrali in situazioni fisiologiche e patologich

Pathway-dependent regulation of sleep dynamics in a network model of the sleep-wake cycle

Sleep is a fundamental homeostatic process within the animal kingdom. Although various brain areas and cell types are involved in the regulation of the sleep-wake cycle, it is still unclear how different pathways between neural populations contribute to its regulation. Here we address this issue by investigating the behavior of a simplified network model upon synaptic weight manipulations. Our model consists of three neural populations connected by excitatory and inhibitory synapses. Activity in each population is described by a firing-rate model, which determines the state of the network. Namely wakefulness, rapid eye movement (REM) sleep or non-REM (NREM) sleep. By systematically manipulating the synaptic weight of every pathway, we show that even this simplified model exhibits non-trivial behaviors: for example, the wake-promoting population contributes not just to the induction and maintenance of wakefulness, but also to sleep induction. Although a recurrent excitatory connection of the REM-promoting population is essential for REM sleep genesis, this recurrent connection does not necessarily contribute to the maintenance of REM sleep. The duration of NREM sleep can be shortened or extended by changes in the synaptic strength of the pathways from the NREM-promoting population. In some cases, there is an optimal range of synaptic strengths that affect a particular state, implying that the amount of manipulations, not just direction (i.e., activation or inactivation), needs to be taken into account. These results demonstrate pathway-dependent regulation of sleep dynamics and highlight the importance of systems-level quantitative approaches for sleep-wake regulatory circuits

The Faculty Notebook, September 2011

The Faculty Notebook is published periodically by the Office of the Provost at Gettysburg College to bring to the attention of the campus community accomplishments and activities of academic interest. Faculty are encouraged to submit materials for consideration for publication to the Associate Provost for Faculty Development. Copies of this publication are available at the Office of the Provost

Modelling sleep-wake regulation: the dynamics, bifurcations and applications of the two process model.

Sleep is essential for most living things to function. Many features of sleep are not yet understood however, mathematical models are playing an important role in developing our understanding of many of the physiological properties of sleep. We introduce the most well-known model of sleep regulation, the two process model which proposes that sleep-wake cycles can be modelled by the interaction between two oscillators. This ostensibly simple model is an interesting example of a nonsmooth dynamical system whose rich dynamical structure has been relatively unexplored. A key aim of this work is to further understand how transitions between monophasic (one sleep a day) and polyphasic (many sleeps a day) sleep occur in the two process model. The two process model can be framed as a one-dimensional map of the circle which, for some parameter regimes, has gaps. As is a feature of continuous circle maps the bifurcation set consists of saddle-node Arnold tongues. We show that border collision bifurcations that arise naturally in maps with gaps extend and supplement these tongues. We see how the periodic solutions that are created by saddle-node bifurcations in continuous maps transition to periodic solutions created by period-adding bifurcations as seen in maps with gaps. With this deeper understanding of the dynamics and bifurcation structure of the two process model we use modified versions of the model to explain two experimental data sets. An ultradian rhythm is a recurrent period or cycle which repeats multiple times across the day. We consider the sleep wake patterns of a the common vole, Microtus Arvalis, which has ultradian rest activity and feeding patterns. By deriving parameters for the two process model from EEG data and sleep/ wake onset times we are able to simulate with high accuracy the key features of spontaneous sleep-wake patterns in the voles. However, to explain phenomena seen in sleep deprivation experiments we include a high amplitude ultradian oscillation alongside the circadian, the results allow us to give some physiological insight into the internal mechanisms which drive sleep/wake onset times in the common vole. Across the human lifespan there are many changes in the physiological properties of sleep, sleep timing and sleep duration. In adolescence sleep timing is delayed and there is a reduction in slow wave sleep which continues into old age as sleep timing gradually becomes earlier. Using a modified two process model which incorporates a van der Pol oscillator driven by external light signals into the circadian process we show that changes in sleep timing and duration across the lifespan can be explained by varying parameters. Model simulation show that these changes can be understood by a simultaneous reduction in the amplitude of the circadian oscillator and the upper asymptote of the homeostatic sleep pressure

How sleep deprivation degrades task performance: combining experimental analysis with simulations of adenosinergic effects of basal ganglia and cortical circuits

Thesis (Ph.D.)--Boston UniversityHumans configure themselves into "neural machines" to perform optimally on distinct tasks, and they excel at maintaining such configurations for brief episodes. The neural configuration needed for peak performance, however, is subject to perturbations on multiple time scales. This thesis reports new empirical analyses and computational modeling to advance understanding of the variations in reaction time (RT) on simple RT tasks that are associated with the duration of the preceding inter-stimulus interval (order of seconds); the time-on-task duration (order of minutes); and sleep deprivation duration (order of hours to days). Responses from the psychomotor vigilance task (PVT), including anticipations (false alarms), normal RTs, and very long RTs (lapses in attention), were analyzed to discover the effects of: the 1 - 9 second inter-stimulus interval (ISI); the 10-minute task session; up to 50 hours of sleep deprivation (SD); and wake-promoting agents, caffeine and modafinil. Normal RTs and lapses in attention were negatively correlated with ISI length, whereas anticipations were positively correlated. Anticipations, normal RTs, and lapses increased as time-on-task increased, and during SD. Both caffeine and modafinil reduced lapses and anticipations during SD and decreased RT variability. A simple neural network model incorporating both a time-dependent inhibitory process and a time-dependent excitatory process was developed. The model robustly simulated the ISI effect on behavior. The SD effects were reproducible with two parameter adjustments. Informed modeling of drug effects required greater neurobiological detail. In the basal ganglia (BG), adenosine accumulation during SD has two notable effects: it antagonizes dopamine to reduce BG responsiveness to incoming cortical signals, and it reduces cholinergic transmission to parietal and prefrontal cortices, thus reducing attention to visual signals. A detailed computational model of interactions between BG and cortex during PVT was developed to simulate effects of adenosine and their amelioration by caffeine. The model simulates drug, ISI and SD effects on anticipations, RTs, and lapses. This model can be used to describe the effects of SD over a wide range of tasks requiring planned and reactive movements, and can predict and model effects of pharmacological agents acting on the adenosinergic, cholinergic and dopaminergic systems

Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission.

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine β-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease