NeuroScience Lecture 5 Rhythms in the brain Ana-Maria Zagrean MD, PhD Assoc. Prof., Division of Physiology & Fundamental Neuroscience Carol Davila University of Medicine and Pharmacy, Bucharest
DEVELOPMENTAL events triggered by spontaneous activity "Cells that fire together, wire together" The blue boxes indicate events that are not linked to the influx of Ca2+ during activity, but rather directly to changes in membrane potential or increases in [Na]i. Red dashed lines and arrows indicate negative-feedback loops. Green dashed lines and arrows indicate positive-feedback loops.
Computation in the brain relies on dynamic interactions between excitatory and inhibitory circuits. Appropriately timed inhibition exerted on specific somatodendritic compartments of principal cells is needed not only to balance excitation, but also for the selective filtering of synaptic excitation, timing of spike output, gain control, governing burst firing and synaptic plasticity, and, at the network level, coordination of cell assemblies through maintenance of oscillations and synchrony. Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition, Sébastien Royer, 2012
Neural oscillation- rhythmic/repetitive neural activity in CNS - triggered by mechanisms localized within individual neurons or by interactions between neurons. - in individual neurons - oscillations in membrane potential or - rhythmic patterns of action potentials, which then produce oscillatory activation of post-synaptic neurons. - in neural networks, synchronized activity of large numbers of neurons can give rise to macroscopic oscillations (which can be observed in the EEG, e.g. alpha activity). Oscillatory activity in groups of neurons generally arises from feedback connections between the neurons that result in the synchronization of their firing patterns. The interaction between neurons can give rise to oscillations at a different frequency than the firing frequency of individual neurons.
Roles of neural oscillations -processing and transfer of neural information, -generation of rhythmic motor output, -feature binding Sensory and other information is represented in the brain by networks of neurons. Neural oscillations have been suggested as the mechanism of neural binding: - neurons within neuronal assemblies fire in synchrony to link different features of neuronal representations together (e.g. shape, motion, colour, depth, and other aspects of perception).
Simulation of neural oscillations at 10 Hz. Spiking of individual neurons (with each dot representing an individual action potential within the population of neurons. The local field potential reflecting the summed activity of individual neurons. Figure illustrates how synchronized patterns of action potentials may result in macroscopic oscillations that can be measured outside the scalp.
Oscillatory activity - levels of organization: 1) the micro-scale (activity of a single neuron), 2) the meso-scale (activity of a local group of neurons) 3) the macro-scale (activity of different brain regions) Provide the basis for sleep spindle generation Thalamocortical feedback loop and the generation of sleep spindles Recordings from individual neurons (Steriade, 1993)
During wakefulness, ascending excitatory input from arousal nuclei to thalamocortical (TC) neurons (red) provides a depolarizing drive that causes thalamocortical neurons and reticular (RT) neurons (blue) to exhibit single-spike tonic firing transfer of information from the periphery up to cortical (Ctx) neurons (black). During wakefulness there is also a descending depolarizing drive onto TC neurons from Ctx neurons.
During deep non-rapid-eye-movement (NREM) sleep, the thalamic relay neurons switch into a burst-firing mode which they adopt by default in the absence of external input. The intrinsic ionic conductances of TC neurons favour a rhythmic burst-firing pattern, which is generated following a hyperpolarizing drive. Because of the extensive connectivity that exists among and between thalamic and Ctx neurons, large populations of neurons are induced to fire in synchrony origin of the slow delta waves that are the EEG signature of deep sleep. During this burst-firing mode, ascending information through the thalamus is blocked. The transition from waking to sleeping involves thalamic oscillations - sleep spindles on EEG, generated when a burst of spikes from a TC neuron impinges on a GABA-ergic RT neuron which then sends a robust inhibitory postsynaptic potential back to the same TC neuron. This hyperpolarizes the cell, which then fires another barrage of spikes on rebound, establishing an oscillation. The length of the inhibitory potential (mediated by GABA type A receptors) determines the time until another burst of spikes is generated by the TC neuron and sets the frequency at 7 14 Hz. Although the TC RT loop is necessary for spindle oscillations, isolated RT neurons can also oscillate with a natural frequency in the same frequency range, and this property might aid spindle generation.
Intrinsic cellular mechanisms of thalamic delta oscillation. (A) Voltage dependency of delta oscillation in a lateroposterior thalamocortical neuron recorded in vivo. The cell oscillates spontaneously at 1.7 Hz. This oscillation is blocked by current depolarization (between arrows) and resumes at removal of the current. The 3 cycles marked by the horizontal line are expanded below. (B) Spontaneous rhythmic burst firing in a neuron recorded in vitro before and after block of voltage-dependent Na + conductances with tetrodotoxin (TTX). (Steriade, 1993.)
http://cercor.oxfordjournals.org/content/14/8/933.long
Time & Rhythms Internal time / biological rhythms determined by the endogenous circadian pacemaker, needs to undergo a daily synchronization with the external time. Studied by chronobiology. External time elapsed time spent awake and asleep that mirrors the homeostatic process.
The dynamics of relationship between different time systems. http://dialogue-associates.com/a-dialogic-model-of-time/
Biological rhythms - comprise biological events with 3 main features: -period (length of a given rhythm); -phase (timing of a given rhythm with respect to a stimulus); -amplitude (measure the amount of a rhythmic event).
Overview of biological circadian clock in humans. Biological clock affects the daily rhythm of many physiological processes. Although circadian rhythms tend to be synchronized with cycles of light and dark, other factors - such as ambient temperature, meal times, stress and exercise - can influence the timing as well.
Circadian Physiology The term circadian is derived from circa (approximately) and dian (daily) ~24 hour rhythms are observed in core body temperature, hormone concentrations (melatonin, cortisol, TSH, PTH and others), subjective alertness, objective performance and other physiologic functions Observed rhythms in these functions are the result of endogenous (circadian) and exogenous (evoked) factors Evoked or masking influences include posture, sleep-wake state, light levels, meals, activity levels Symptoms of misalignment are observed in jet lag and shift work Safety (worker and others) Health (cardiovascular, hormone, gastrointestinal abnormalities)
Circadian rhythm (CR) - The 24 h CR in humans is tuned with the 24-h solar light-dark cycle (the most important recurring environmental stimulus - photoentrainment). - depend on genetically controlled rhythmic molecular events in the internal clock that rule cellular, system, and behavioral functions. one fundamental behavioral CR, sleep-wake cycle, is a physiological period of quiescence, with roles not yet well understood.
Circadian rhythm - Sleep-wake cycle Along with the internal circadian control of the sleep-wake rhythm, the amount of time spent awake and asleep/24 h is under a homeostatic control sleep propensity increases with elapsed time awake/dissipates with elapsed time asleep during the following sleep episode. Independent of internal time (circadian phase), in an adult: - the max capacity to stay awake is around 16 h - the max capacity to maintain a sleep efficiency of 90% is around 8 h Napping during the day Poor sleep - Sleep debt consequences of fatigue on reaction time, judgement, behaviour Obs role REM sleep in early development ; muscle atonia
http://www.scienzagiovane.unibo.it/english/sleep/3-sleep-animals.html
Sleep is a series of precisely controlled physiological states, a highly conserved behaviour which offers advantages that outweigh the disadvantage of becoming vulnerable during sleep Then, why we sleep? Role of sleep in preventing the waking brain of synaptic overload or cellular stress, in regulating cortical synaptic plasticity. Memory consolidation by increased strength of synaptic connections induced by experiences during waking hours. Cognitive abilities, behavioral performance, mood, immune defence, insulin regulation, weight control are altered in sleep deprivation (documented voluntary sleeplessness w/o pharmacol stim. 264 h/11 days) Restorative role, energy conservation, replenish glycogen brain levels, allow low energy consume to keep the body warm during colder nights (minimum body temp. at night to reduce heat loss) - thermoregulation. O2 consume decreased during sleep. Still, the underlining basis for the sleep homeostatic function remains uncertain
Consciousness and the Sleeping Brain Consciousness is a person s subjective awareness of both their inner thinking and feeling and their external environment Sleep: Active process Composed of two major states (possible to recognize on EEG recording) Rapid Eye Movement (REM) Sleep - high levels of brain activity Non-REM Sleep NREM sleep stages 1-4» Stages 3&4 are known as deep sleep or Slow Wave Sleep Timing and state of sleep depend on Length of time awake Circadian time
Why do we dream? Explanations for dreaming : Sigmund Freud proposed that dreams were disguised passages for inner conflicts of our unconscious mind, a view not accepted by modern sleep researchers The activation-synthesis hypothesis contends that dreams are merely the sleeping brain s attempt to make sense of random neural activity without the rational interpretation of the frontal lobe (without considering all the details)
Location of the internal clock: Suprachiasmatic nucleus (SCN) the master pacemaker Suprachiasmatic nucleus (SCN) of the hypothalamus, receiving inputs from the retina 2 small clusters /nuclei of ~10,000 neurons each (left and right) lying just above the optic chiasm, at the base of diencephalon
Basic Properties of Circadian rhythms Periodicity of approximately 24 h Endogenous generation SCN exhibits endogenous rhythmicity Entrainment by environmental time cues/signals Rhythm has been entrained by prior light:dark cycle Temperature compensation
Basic requirements for a circadian pacemaker Intrinsic rhythmicity - endogenously rhythmic in vivo or in vitro Dispersed SCN cells in vitro exhibit circadian rhythms in firing rate Entrained by environmental signals light and other zeitgeber (time givers) Capable of driving evident circadian rhythms The SCN is necessary for most overt circadian rhythms in mammals
Dispersed SCN cells in vitro exhibit circadian rhythms in firing rate Time (h) Welsch et al, 1995
Can the SCN restore rhythms to an arrythmic animal? Remove SCN (Suprachiasmatic nucleus) Arrhythmic patterns of locomotion, feeding, hormone secretion Implant donor SCN tissue Return rhythms of donor hamster
SCN lesions ablate circadian rhythms Pineal NAT SCNX Moore and Klein, 1974
Circadian rhythmicity - suprachiasmatic nucleus (SCN) Individual neurons in SCN generate a 24-hour rhythm. These are linked to generate a single output rhythm. Primary input pathway to the SCN is a monosynaptic pathway from retina to hypothalamus (retino-hypothalamic tract - RHT) from non-image forming ganglion cells in retina containing melanopsin (non-rod, non-cone photoreceptor) Destruction of both SCN causes arrhythmicity SCN also receives connections from the pineal gland.
A unique population of ganglion cells that contain light sensitive melanopsin transduces light in the retina retino-hypothalamic projections suprachiasmatic nuclei (SCN) in the hypothalamus (HT): synchronize the circadian activity of SCN neurons with the daily cycle of light and dark. SCN neural projections are largely oriented towards the HT: SCN is dependent upon relays that integrate a variety of sensory information important for the temporal organization of diverse functions regulated by the HT ( circadian timing system ).
SCN is capable of communicating timing information to drive an overt rhythm retino-hypothalamic projections Circadian timing system (CTS). The control feature of the CTS is the circadian pacemaker. Information from photoreceptors is conveyed by entrainment pathways to the pacemaker. The pacemaker has a rhythmic output that drives "slave" oscillators, which control functions that exhibit circadian regulation.
SCN is capable of communicating timing information to drive an overt rhythm
SCN in mammals Circadian outputs Photic input The retinal ganglion cells also project to the intergeniculate leaflet (IGL) Arousal related input (1) Core/central area: colocalization GABA + VIP or GRP (gastrin-releasing peptide) (2) Shell/peripheral area: colocalization GABA + arginin vasopresine (AVP) or calretinin (CAR - a vit. D-dependent calcium-binding protein involved in Ca signaling) Glu, glutamate; 5HT, serotonin; ACH, acetylcholine; NA, noradrenaline; NPY, neuropeptide Y; VIP, Vasoactive intestinal peptide.
Circadian regulation of ion channels and their functions This diagram illustrates a general model of the mammalian circadian oscillator in the SCN. The molecular clock is composed of interlocking transcription translation feedback loops. CLOCK and BMAL1 (Mop3) are two basic helix-loop-helix-pas (Period-Arnt-Single-minded) transcription factors, and Bmal1 is maximally expressed during the middle of the night. CLOCK and BMAL1 form heterodimers and activate the transcription of downstream genes containing E-box cis regulatory enhancer sequences in their promoter regions, including the Period (Per1/Per2/Per3) and Cryptochrome (Cry1/Cry2) genes. The transcript levels of both Pers and Crys reach their peak during mid to late day, which are anti-phase to Bmal1 expression. Two members of the casein kinase Iδ and Iε family are involved in post-translational phosphorylation of PERs and ultimately contribute to their degradation. The PERs, CRYs, and other proteins form heteromultimeric complexes that translocate into the nucleus and directly abrogate the transcriptional activity of the CLOCK BMAL1 complex, thereby lowering Per and Cry mrna levels. Thus, PERs, CRYs, and associated proteins regulate their own transcription through the inhibition of transcriptional activity of the CLOCK BMAL1 heterodimers. Another feedback loop includes the retinoic acid-related orphan nuclear receptor, REV ERBα, which also is one of the downstream genes activated by CLOCK BMAL1 heterodimers. The REV ERBα protein represses Bmal1 gene expression through binding the retinoic acid-related orphan receptor response elements (ROREs) in Bmal1 s promoter. Therefore, BMAL1 attenuates its own transcription by transcriptional activation of REV ERBα. Collectively, these positive and negative feedback loops are the major components of the mammalian molecular clock. They play critical roles in establishing the circadian rhythm (figure is modified from Lowrey and Takahashi 2004).
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The pineal gland
Production of melatonin in the pineal gland: a single pinealocyte, the endocrine unit of the gland. A series of neurons connect the eyes to the pineal gland. Norepinephrine released from sympathetic nerves stimulates β-adrenergic receptor on the pineal cell membrane. This caused an activation of adenylate cyclase inside the cell to form camp from ATP. The specific enzyme regulated by the β-adrenergic receptor was found to be NAT, the enzyme that converts serotonin to N-acetylserotonin. This latter compound serves as the substrate for hydroxyindole- O-methyltransferase (HIOMT), that forms melatonin, which is primarily produced at night, and is quickly released into the circulation once it is formed (Axelrod, 1975; Reiter et al., 1994).
Circadian Phase Markers Active investigation into markers of circadian phase in humans Clinical utility of markers Two currently utilized markers Core body temperature Dim light melatonin measurement (DLMO)
Core Body temperature Drop in temp associated with stability in sleep Three dips in temp 8:00pm-12:00am 3:00-5:00am 1:00-4:00pm
Melatonin Secretion Increase in levels around 8:00pm Levels peak at approximately 3:00am and begin to decrease Lowest levels just before awakening
Circadian Phase Markers Measurement of markers difficult Core body temperature altered by activity, food intake, and sleep Melatonin secretion very sensitive to light exposure, needs to be obtained under dim light conditions Dim light melatonin onset (DLMO) Disruptions in the circadian rhythm physiology consequently can cause a number of circadian rhythm sleep disorders Disorders can be secondary to external inference with sleep wake mechanism Remainder of disorders are related to inherent disruption of the circadian rhythm
Maternal rhythm of melatonin is one of the time signals to the fetus (maternal melatonin is a Zeitgeber for the fetal SCN) Circadian rhythms in the fetus. Mol Cell Endocrinol. 2012 Feb 5;349(1):68-75. Serón-Ferré M, Mendez N, Abarzua-Catalan L, Vilches N, Valenzuela FJ, Reynolds HE, Llanos AJ, Rojas A, Valenzuela GJ, Torres- Farfan C. Throughout gestation, the close relationship between mothers and their progeny ensures adequate development and a successful transition to postnatal life. By living inside the maternal compartment, the fetus is inevitably exposed to rhythms of the maternal internal milieu such as temperature; rhythms originated by maternal food intake and maternal melatonin, one of the few maternal hormones that cross the placenta unaltered. The fetus, immature by adult standards, is however perfectly fit to accomplish the dual functions of living in the uterine environment and developing the necessary tools to "mature" for the next step, i.e. to be a competent newborn. In the fetal physiological context, organ function differs from the same organ's function in the newborn and adult. This may also extend to the developing circadian system. The information reviewed here suggests that the fetal circadian system is organized differently from that of the adult. Moreover, the fetal circadian rhythm is not just present simply as the initial immature expression of a mechanism that has function in the postnatal animal only. We propose that the fetal suprachiasmatic nucleus (SCN) of the hypothalamus and fetal organs are peripheral maternal circadian oscillators, entrained by different maternal signals. Conceptually, the arrangement produces internal temporal order during fetal life, inside the maternal compartment. Following birth, it will allow for postnatal integration of the scattered fetal circadian clocks into an adult-like circadian system commanded by the SCN. PMID: 21840372
The SCN and behavioral state control. The SCN projects to the ventrolateral preoptic area (VLPO), an area mediating sleep. VLPO inhibits the arousal activity of the tuberomammillary nucleus during sleep. The SCN provides an arousal-promoting input to the posterior hypothalamic area, particularly to hypocretin neurons, which project upon the neocortex and subcortical arousal areas.
Timing Multiple input pathways to the circadian clock transmit various kinds of timing information Light Activity and arousal Multiple output pathways from the clock regulate various overt circadian rhythms Sleep-wake cycles Body temperature rhythms Hormone rhythms
Robust, well-synchronized circadian rhythms promote health, well-being, and optimal performance. Timing is everything!