Time in the biological sense is measured by cycles that range from milliseconds to years. Circadian rhythms, which measure time on a scale of 24 h, are generated by one of the most ubiquitous and well-studied timing systems. At the core of this timing mechanism is an intricate molecular mechanism that ticks away in many different tissues throughout the body. However, these independent rhythms are tamed by a master clock in the brain, which coordinates tissue-specific rhythms according to light input it receives from the outside world.

Coordination of circadian timing in mammals

https://sites.oxy.edu/clint/physio/article/neurobiologyofdepression.pdf

Neurobiology of depression.

Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.

https://www.springer.com/cda/content/document/cda_downloaddocument/9783642259494-c1.pdf?SGWID=0-0-45-1387410-p174273964

Molecular components of the mammalian circadian clock

Our understanding of the cellular implementation of systems-level neural processes like action, thought and emotion has been limited by the availability of tools to interrogate specific classes of neural cells within intact, living brain tissue. Here we identify and develop an archaeal light-driven chloride pump (NpHR) from Natronomonas pharaonis for temporally precise optical inhibition of neural activity. NpHR allows either knockout of single action potentials, or sustained blockade of spiking. NpHR is compatible with ChR2, the previous optical excitation technology we have described, in that the two opposing probes operate at similar light powers but with well-separated action spectra. NpHR, like ChR2, functions in mammals without exogenous cofactors, and the two probes can be integrated with calcium imaging in mammalian brain tissue for bidirectional optical modulation and readout of neural activity. Likewise, NpHR and ChR2 can be targeted together to Caenorhabditis elegans muscle and cholinergic motor neurons to control locomotion bidirectionally. NpHR and ChR2 form a complete system for multimodal, high-speed, genetically targeted, all-optical interrogation of living neural circuits.

Multimodal fast optical interrogation of neural circuitry

The suprachiasmatic nucleus (SCN) controls the circadian rhythm of physiological and behavioural processes in mammals. Here we show that prokineticin 2 (PK2), a cysteine-rich secreted protein, functions as an output molecule from the SCN circadian clock. PK2 messenger RNA is rhythmically expressed in the SCN, and the phase of PK2 rhythm is responsive to light entrainment. Molecular and genetic studies have revealed that PK2 is a gene that is controlled by a circadian clock (clock-controlled). Receptor for PK2 (PKR2) is abundantly expressed in major target nuclei of the SCN output pathway. Inhibition of nocturnal locomotor activity in rats by intracerebroventricular delivery of recombinant PK2 during subjective night, when the endogenous PK2 mRNA level is low, further supports the hypothesis that PK2 is an output molecule that transmits behavioural circadian rhythm. The high expression of PKR2 mRNA within the SCN and the positive feedback of PK2 on its own transcription through activation of PKR2 suggest that PK2 may also function locally within the SCN to synchronize output.

Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus

The melanin-concentrating hormone (MCH) system is thought to be an important regulator of food intake. Recently the orphan G protein-coupled receptor SLC-1 was identified as the MCH receptor (MCHR). Preliminary analyses of MCHR mRNA distribution have supported a role for the MCH system in nutritional homeostasis. We report here a complete anatomical distribution of the MCHR mRNA. We have found high levels of expression of MCHR mRNA in most anatomical areas implicated in control of olfaction, with the exception of the main olfactory bulb. Dense labeling was also detected in the hippocampal formation, subiculum, and basolateral amygdala, all of which are important in learning and memory, and in the shell of the nucleus accumbens, a substrate for motivated behavior and feeding. Within the hypothalamus, MCHR mRNA was moderately expressed in the ventromedial nucleus, arcuate nucleus, and zona incerta, all of which serve key roles in the neuronal circuitry of feeding. In the brainstem, strong expression was observed in the locus coeruleus, which is implicated in arousal, as well as in nuclei that contribute to orofacial function and mastication, including the facial, hypoglossal, motor trigeminal, and dorsal motor vagus nuclei. In most regions there was a good correspondence between MCHR mRNA distribution and that of MCH-immunoreactive fibers. Taken together, these data suggest that MCH may act at various levels of the brain to integrate various aspects of feeding behavior. However, the extensive MCHR distribution throughout the brain suggests that this receptor may play a role in other functions, most notably reinforcement, arousal, sensorimotor integration, and autonomic control. J. Comp. Neurol. 435:26–40, 2001. © 2001 Wiley-Liss, Inc.

Expression of the melanin‐concentrating hormone (MCH) receptor mRNA in the rat brain

Neurogenesis persists in the olfactory bulb (OB) of the adult mammalian brain. New interneurons are continually added to the OB from the subventricular zone (SVZ) via the rostral migratory stream (RMS). Here we show that secreted prokineticin 2 (PK2) functions as a chemoattractant for SVZ-derived neuronal progenitors. Within the OB, PK2 may also act as a detachment signal for chain-migrating progenitors arriving from the RMS. PK2 deficiency in mice leads to a marked reduction in OB size, loss of normal OB architecture, and the accumulation of neuronal progenitors in the RMS. These findings define an essential role for G protein-coupled PK2 signaling in postnatal and adult OB neurogenesis.

https://science.sciencemag.org/content/sci/308/5730/1923.full.pdf

Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling.

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.

https://www.pnas.org/content/pnas/111/35/12913.full.pdf

Optogenetic neuronal stimulation promotes functional recovery after stroke

Circadian clocks drive daily rhythms in virtually all organisms. In mammals, the suprachiasmatic nucleus (SCN) is recognized as the master clock that synchronizes central and peripheral oscillators to evoke circadian rhythms of diverse physiology and behavior. How the timing information is transmitted from the SCN clock to generate overt circadian rhythms is essentially unknown. Prokineticin 2 (PK2), a clock-controlled gene that encodes a secreted protein, has been indicated as a candidate SCN clock output signal that regulates circadian locomotor rhythm. Here we report the generation and analysis of PK2-null mice. The reduction of locomotor rhythms in PK2-null mice was apparent in both hybrid and inbred genetic backgrounds. PK2-null mice also displayed significantly reduced rhythmicity for a variety of other physiological and behavioral parameters, including sleep–wake cycle, body temperature, circulating glucocorticoid and glucose levels, as well as the expression of peripheral clock genes. In addition, PK2-null mice showed accelerated acquisition of food anticipatory activity during a daytime food restriction. We conclude that PK2, acting as a SCN output factor, is important for the maintenance of robust circadian rhythms.

https://www.jneurosci.org/content/jneuro/26/45/11615.full.pdf

Michelle Y. Cheng

Papers

Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus

Expression of the melanin‐concentrating hormone (MCH) receptor mRNA in the rat brain

Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling.

Optogenetic neuronal stimulation promotes functional recovery after stroke

Attenuated circadian rhythms in mice lacking the Prokineticin 2 gene