The hedgehog (HH) family of growth factors is involved in many aspects of growth and development, from the establishment of left-right axes at gastrulation to the patterning and formation of multiple structures in essentially every tissue and the maintenance and regulation of stem cell populations in adults. Sonic hedgehog (Shh) in particular acts as a mitogen, regulating proliferation of target cells, a growth factor that triggers differentiation in target populations, and a morphogen causing cells to respond differently based on their positions along a spatial and temporal concentration gradient. Given its very broad range of effects in development, it is not surprising that many of the structures affected by a disruption in Shh signaling are also affected in Down syndrome (DS). However, recent studies have shown that trisomic cerebellar granule cell precursors have a deficit, compared to their euploid counterparts, in their response to the mitogenic effects of Shh. This deficit substantially contributes to the hypocellular cerebellum in mouse models that parallels the human DS phenotype, and can be corrected in early development by a single exposure to a small molecule agonist of the Shh pathway.
Orexin, a small neuropeptide released from neurons in the hypothalamus with widespread projections throughout the central nervous system, has broad biological roles including the modulation of breathing and autonomic function. That orexin activity is fundamentally dependent on sleep-wake state and circadian cycle requires consideration of orexin function in physiological control systems in respect to these two state-related activity patterns. Both transgenic mouse studies and focal orexin receptor antagonism support a role for orexins in respiratory chemosensitivity to CO2 predominantly in wakefulness, with further observations limiting this role to the dark period. In addition, orexin neurons participate in the regulation of sympathetic activity, including effects on blood pressure and thermoregulation. Orexin is also essential in physiological responses to stress. Orexin-mediated processes may operate at two levels: 1) in sleep-wake and circadian states; and 2) in stress, e.g., the defense or “fight or flight” response and panic anxiety syndrome.
orexin; Almorexant; chemoreception; CO2; blood pressure
We can learn about the evolution of neocortex in primates through comparative studies of cortical organization in primates and those mammals that are the closest living relatives of primates, in conjunction with brain features revealed by the skull endocasts of fossil archaic primates. Such studies suggest that early primates had acquired a number of features of neocortex that now distinguish modern primates. Most notably, early primates had an array of new visual areas, and those visual areas widely shared with other mammals had been modified. Posterior parietal cortex was greatly expanded with sensorimotor modules for reaching, grasping, and personal defense. Motor cortex had become more specialized for hand use, and the functions of primary motor cortex were enhanced by the addition and development of premotor and cingulate motor areas. Cortical architecture became more varied, and cortical neuron populations became denser overall than in nonprimate ancestors. Primary visual cortex had the densest population of neurons, and this became more pronounced in the anthropoid radiation. Within the primate clade, considerable variability in cortical size, numbers of areas, and architecture evolved.
prosimians; tarsiers; anthropoids; sensory cortex; motor cortex
Epidemiological studies show that adverse cardiovascular events peak in the morning (i.e., between 6 AM and noon) and that shift work is associated with cardiovascular disease, obesity, and diabetes. The endogenous circadian timing system modulates certain cardiovascular risk markers to be highest (e.g., cortisol, nonlinear dynamic heart rate control, and platelet activation) or to respond most unfavorably to stressors such as exercise (e.g., epinephrine, norepinephrine, and vagal cardiac modulation) at an internal body time corresponding to the time of day when adverse cardiovascular events most likely occur. This indicates that the circadian timing system and its interaction with external cardiovascular stressors (e.g., physical activity) could contribute to the morning peak in adverse cardiovascular events. Moreover, circadian misalignment and simulated night work have adverse effects on cardiovascular and metabolic function. This suggests that misalignment between the behavioral cycle and the circadian timing system in shift workers contributes to that population’s increased risk for cardiometabolic disease.
biological clock; circadian misalignment; glucose metabolism; heart; night work; shift work; suprachiasmatic nucleus
A panic response is an adaptive response to deal with an imminent threat and consists of an integrated pattern of behavioral (aggression, fleeing or freezing) and increased cardiorespiratory and endocrine responses that are highly conserved across vertebrate species. In the 1920’s and 1940’s Philip Bard and Walter Hess respectively determined that the posterior regions of the hypothalamus are critical for a “fight-or-flight” reaction to deal with an imminent threat. Since the 1940’s it was determined that the posterior hypothalamic panic area was located dorsal (perifornical nucleus: PeF) and dorsomedial (dorsomedial hypothalamus: DMH) to the fornix. This area is also critical for regulating circadian rhythms and in 1998, a novel wake-promoting neuropeptide called orexin/hypocretin (ORX) was discovered and determined to be almost exclusively synthesized in the DMH/PeF and adjacent lateral hypothalamus. The most proximally emergent role of ORX is in regulation of wakefulness through interactions with efferent systems that mediate arousal and energy homeostasis. A hypoactive ORX system is also linked to narcolepsy. However, ORX’s role in more complex emotional responses is emerging in more recent studies where ORX is linked to depression and anxiety states. Here we review data that, demonstrates ORX’s ability to mobilize a coordinated adaptive panic/defence response (anxiety, cardiorespiratory and endocrine components), and summarize the evidence that supports a hyperactive ORX system being linked to pathological panic and anxiety states.
Sleep, which is evolutionarily conserved across species, is a biological imperative that cannot be ignored or replaced. However, the percentage of habitually sleep-restricted adults has increased in recent decades. Extended work hours and commutes, shift work schedules, and television viewing are particularly potent social factors that influence sleep duration. Chronic partial sleep restriction, a product of these social expediencies, leads to the accumulation of sleep debt over time and consequently increases sleep propensity, decreases alertness, and impairs critical aspects of cognitive functioning. Significant interindividual variability in the neurobehavioral responses to sleep restriction exists—this variability is stable and phenotypic—suggesting a genetic basis. Identifying vulnerability to sleep loss is essential as many adults cannot accurately judge their level of impairment in response to sleep restriction. Indeed, the consequences of impaired performance and the lack of insight due to sleep loss can be catastrophic. In order to cope with the effects of social expediencies on biological imperatives, identification of biological (including genetic) and behavioral markers of sleep loss vulnerability as well as development of technological approaches for fatigue management are critical.
sleep deprivation; sleep duration; neurobehavioral functions; fatigue management; individual differences; genetics; biomarkers
Basic tendencies to detect and respond to significant events are present in the simplest single cell organisms, and persist throughout all invertebrates and vertebrates. Within vertebrates, the overall brain plan is highly conserved, though differences in size and complexity also exist. The forebrain differs the most between mammals and other vertebrates. The classic notion that the evolution of mammals led to radical changes such that new forebrain structures (limbic system and neocortex) were added has not held up, nor has the idea that so-called limbic areas are primarily involved in emotion. Modern efforts have focused on specific emotion systems, like the fear or defense system, rather than on the search for a general purpose emotion systems. Such studies have found that fear circuits are conserved in mammals, including humans. Animal work has been especially successful in determining how the brain detects and responds to danger. Caution should be exercised when attempting to discuss other aspects of emotion, namely subjective feelings, in animals since there are no scientific ways of verifying and measuring such states except in humans.
The nonhuman primate brain, the model system closest to the human brain, plays a critical role in our understanding of neural computation, cognition, and behavior. The continued quest to crack the neural codes in the monkey brain would be greatly enhanced with new tools and technologies that can rapidly and reversibly control the activities of desired cells at precise times during specific behavioral states. Recent advances in adapting optogenetic technologies to monkeys have enabled precise control of specific cells or brain regions at the millisecond timescale, allowing for the investigation of the causal role of these neural circuits in this model system. Validation of optogenetic technologies in monkeys also represents a critical preclinical step on the translational path of new generation cell-type-specific neural modulation therapies. Here, I discuss the current state of the application of optogenetics in the nonhuman primate model system, highlighting the available genetic, optical and electrical technologies, and their limitations and potentials.
monkey; genetic manipulation; optical; channelrhodopsin; archaerhodopsin; halorhodopsin; rat
The ability to silence, in a temporally precise fashion, the electrical activity of specific neurons embedded within intact brain tissue, is important for understanding the role that those neurons play in behaviors, brain disorders, and neural computations. “Optogenetic” silencers, genetically encoded molecules that, when expressed in targeted cells within neural networks, enable their electrical activity to be quieted in response to pulses of light, are enabling these kinds of causal circuit analyses studies. Two major classes of optogenetic silencer are in broad use in species ranging from worm to monkey: light-driven inward chloride pumps, or halorhodopsins, and light-driven outward proton pumps, such as archaerhodopsins and fungal light-driven proton pumps. Both classes of molecule, when expressed in neurons via viral or other transgenic means, enable the targeted neurons to be hyperpolarized by light. We here review the current status of these sets of molecules, and discuss how they are being discovered and engineered. We also discuss their expression properties, ionic properties, spectral characteristics, and kinetics. Such tools may not only find many uses in the quieting of electrical activity for basic science studies, but may also, in the future, find clinical uses for their ability to safely and transiently shut down cellular electrical activity in a precise fashion.
optogenetics; opsins; neural silencing; halorhodopsin; archaerhodopsin; channelrhodopsin; control; cell types; neural circuits; causality
This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations.
Down syndrome; brain development; seizures; hypotonia; dementia; clinical trials
Fluorescent protein technology has evolved to include genetically-encoded biosensors that can monitor levels of ions, metabolites, and enzyme activities as well as protein conformation and even membrane voltage. They are well suited to live-cell microscopy and quantitative analysis, and they can be used in multiple imaging modes, including one or two-photon fluorescence intensity or lifetime microscopy. Although not nearly complete, there now exists a substantial set of genetically-encoded reporters that can be used to monitor many aspects of neuronal and glial biology, and these biosensors can be used to visualize synaptic transmission and activity-dependent signaling in vitro and in vivo. In this review we present an overview of design strategies for engineering biosensors, including sensor designs using circularly-permuted fluorescent proteins and using fluorescence resonance energy transfer (FRET) between fluorescent proteins. We also provide examples of indicators that sense small ions (e.g., pH, chloride, zinc), metabolites (e.g., glutamate, glucose, ATP, cAMP, lipid metabolites), signaling pathways (e.g., G protein coupled receptors, Rho GTPases), enzyme activities (e.g., protein kinase A, caspases), and reactive species. We focus on examples where these genetically-encoded indicators have been applied to brain-related studies and used with live-cell fluorescence microscopy.
Genetically-encoded; biosensor; fluorescent protein; circularly-permute; resonance energy transfer; FRET; live-cell microscopy
The tremendous shifts in the size, structure, and function of the brain during primate evolution are ultimately caused by changes at the genetic level. Understanding what these changes are and how they effect the phenotypic changes observed lies at the heart of understanding evolutionary change. This chapter focuses on understanding the genetic basis of primate brain evolution, considering the substrates and mechanisms through which genetic change occurs. It also discusses the implications that our current understandings and tools have for what we have already discovered and where our studies will head in the future. While genetic and genomic studies have identified many regions undergoing positive selection during primate evolution, the findings are certainly not exhaustive and functional relevance remains to be confirmed. Nevertheless, a strong foundation has been built upon which future studies will emerge.
Genetic evolution; molecular evolution; catarrhine; hominoid; hominin; FOXP2; microcephaly; opsin; olfaction; pleiotropy; gene regulation; divergence; polymorphism
A major challenge in neuroscience is to understand how universal behaviors, such as sensation, movement, cognition, and emotion, arise from the interactions of specific cells that are present within intricate neural networks in the brain. Dissection of such complex networks has typically relied on disturbing the activity of individual gene products, perturbing neuronal activities pharmacologically, or lesioning specific brain regions, to investigate the network’s response in a behavioral output. Though informative for many kinds of studies, these approaches are not sufficiently fine-tuned for examining the functionality of specific cells or cell classes in a spatially or temporally-restricted context. Recent advances in the field of optogenetics now enable researchers to monitor and manipulate the activity of genetically defined cell populations with the speed and precision uniquely afforded by light. Transgenic mice engineered to express optogenetic tools in a cell type-specific manner offer a powerful approach for examining the role of particular cells in discrete circuits in a defined and reproducible way. Not surprisingly then, recent years have seen substantial efforts directed towards generating transgenic mouse lines that express functionally relevant levels of optogenetic tools. In this chapter, we review the state of these efforts and consider aspects of the current technology that would benefit from additional improvement.
transgenic mice; genetic manipulation; cell type; Cre; channelrhodopsin; halorhodopsin; archaerhodopsin; calcium indicator; voltage sensor
Brain size, body size, developmental length, life span, costs of raising offspring, behavioral complexity, and social structures are correlated in mammals due to intrinsic life-history requirements. Dissecting variation and direction of causation in this web of relationships often draw attention away from the factors that correlate with basic life parameters. We consider the “social brain hypothesis,” which postulates that overall brain and the isocortex are selectively enlarged to confer social abilities in primates, as an example of this enterprise and pitfalls. We consider patterns of brain scaling, modularity, flexibility of brain organization, the “leverage,” and direction of selection on proposed dimensions. We conclude that the evidence supporting selective changes in isocortex or brain size for the isolated ability to manage social relationships is poor. Strong covariation in size and developmental duration coupled with flexible brains allow organisms to adapt in variable social and ecological environments across the life span and in evolution.
evolution; primate; cortex; social; variation