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PubMed2002

The concept of sickness behavior: a brief chronological account of four key discoveries.

Neurons do not have receptors to detect bacteria or viruses, yet the presence of these microorganisms can cause a sickness behavior syndrome that includes, e.g., fever, anorexia, and lethargy. Because the immune system has receptors capable of detecting these non-cognitive stimuli, how the immune system transmits a message to the brain has been studied to understand why behavior is altered in sick animals. The focus has been on several cytokines secreted by leukocytes; these include interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). These cytokines are secreted by activated mononuclear phagocytic cells, and numerous studies show that both peripheral and central injection of IL-1beta, IL-6, and TNF-alpha induce sickness behavior. Moreover, these cytokines and their receptors are present in the brain and inhibiting the secretion of cytokines or blocking their receptors in the brain blocks or abrogate the behavioral responses induced by inflammatory stimuli. Because the sickness behavior syndrome modulates the immune system and enhances recovery, the interplay between the immune system and central nervous system is an essential part of the overall host defense against pathogenic microorganisms. The purpose of this brief paper is to provide a chronological description of four critical advances that have led to the current understanding of how the immune system communicates with the brain to induce sickness behavior. Results from several key studies will be discussed, which showed that: (1) sickness behavior is a motivational state; (2) sickness behavior is a well-organized adaptive response to infection; (3) cytokines produced by activated leukocytes induce sickness behavior; and (4) cytokines transmit messages from the periphery to the brain using humoral and neural pathways.

Adaptation, Physiological↗

PubMed1997

[Central nervous system control of erection].

Relaxation of arterial and cavernous smooth muscle fibers, leading to the filling of the sinusoidal spaces with blood, are the local mechanisms of erection. Smooth muscle relaxation results from activation of parasympathetic neural pathway and probably simultaneous inhibition of the sympathetic outflow. Reflexive erection elicited by recruitment of penile afferents conveyed by the dorsal penile nerve involves both autonomic and somatic efferents. This reflex is mediated at the spinal cord level and modulated by supraspinal influences. Serotonergic pathways originating in the raphe nuclei mediate inhibitory control on reflexive erection. Several hypothalamic areas such as the medial preoptic area and the paraventricular nucleus are the source of descending pathways and/or represent important integrating centers. Dopamine acting at the medial preoptic area level may regulate penile erection. Neuroendocrine regulation may vary depending on the context in which erection occurs, for example, coitus, in response to extrinsic or psychogenic stimuli, and rapid eye movement sleep.

Afferent Pathways↗

PubMed1997

Induction of periodic alternating nystagmus in intact goldfish by sinusoidal rotation.

During movement, the vestibulo-ocular reflex (VOR) normally maintains retinal image stability by making slow-phase eye rotations that counterbalance head rotations. These eye rotations are nystagmic when the on-going slow-phases are interrupted by fast-phase eye rotations that reset eye position. Periodic alternating nystagmus (PAN) is an eye-movement disorder characterized by uncontrollable nystagmus that alternates direction roughly sinusoidally (at about 0.005 Hz). PAN has been observed only in humans with cerebellar disorders and in monkeys with lesions to the cerebellar nodulus and uvula. We show experimentally in intact goldfish that prolonged rotation in darkness for 1 h at specific frequencies (0.05-0.1 Hz) induces PAN, upon which the normal VOR response is superimposed. We show computationally that rotation-induced PAN may result from decreased cerebellar inhibition of VOR brain stem neural pathways.

Animals↗

PubMed1998

Mapping of neural and signal transduction pathways for lordosis in the search for estrogen actions on the central nervous system.

Estrogen can act on the brain to regulate various biological functions and behavior. In attempts to elucidate the estrogen action, the rodent female reproductive behavior, lordosis, was used as a model. Lordosis is an estrogen-dependent reflexive behavior and, hence, is mediated by discrete neural pathways that are modulated by estrogen. Therefore, a strategy of mapping the pathways, both neural and biochemical, and examining them for estrogen effect was used to localize and subsequently analyze the central action of estrogen. Using various experimental approaches, an 'inverted Y-shaped' neural pathway both sufficient and essential for mediating lordosis was defined. The top portion is a descending pathway conveying the permissive estrogen influence which originated from hypothalamic ventromedial nucleus relayed via midbrain periaqueductal grey down to medullary reticular formation, the top of the spino-bulbo-spinal reflex arc at the bottom. This estrogen influence alters the input-output relationship, shifting the output toward more excitation. With this shift in output, estrogen can enable the otherwise ineffective lordosis-triggering sensory stimuli to elicit lordosis. In the ventromedial nucleus, the origin of the estrogen influence, a multidisciplinary approach was used to map intracellular signaling pathways. A phosphoinositide pathway involving a specific G protein and the activation of protein kinase C was found to be involved in the mediation of lordosis as well as a probable target of the permissive estrogen action. The action of estrogen on this signal transduction pathway, a potentiation, is consistent with and, hence, may be an underlying mechanism for the estrogen influenced shift toward excitation. Thus, further investigation on this specific signal transduction pathway should be helpful in elucidating the action of estrogen on the brain.

Animals↗

PubMed1977

Adrenocortical responses to olfactory stimulation in rats with partial hypothalamic deafferentations and lesions.

Previous experiments from this laboratory using complete hypothalamic deafferentation have demonstrated that the adrenocortical discharge following olfactory stimulation is essentially mediated by neural pathways. In order to identify the neural afferents and the hypothalamic areas involved, this response was studied in rats with anterior (AD) and posterior (PD) partial hypothalamic deafferentations as well as in animals with bilateral lesions in the ventrolateral medial forebrain bundle (VMFB) and the gemini region (GR) in the hypothalamus. While rats with PD had a normal adrenocortical response to odor stimulation, this was completely inhibited in animals with AD and partially reduced in VMFB and GR lesioned rats. These data would indicate that the adrenocortical response following olfactory stimulation is mediated by anterior afferents to the hypothalamus and involves the VMFB and GR.

Animals↗

PubMed1991

Expression of the guanine nucleotide-binding protein Go correlates with the state of neural competence in the amphibian embryo.

The nucleotide-binding protein Go is a transducing molecule closely associated with neural structures in vertebrates. Because of the potential importance of molecules of this type during the first step of neurogenesis, we have investigated the kinetics of expression of Go in the amphibian (Pleurodeles waltl) embryo, focusing our attention on the stages corresponding to the acquisition of neural competence by presumptive ectoderm and to the process of neural induction. Using affinity-purified IgGs directed against the alpha subunit of Go, Go-like immunoreaction (GoLI) is first detected at the midblastula stage in some animal cap (future ectodermal) cells just before they have attained competence to be neuralized. At the early gastrula stage, GoLI is almost exclusively expressed by neural-competent tissue as a whole, with no obvious difference between the dorsal (prospective neural) and the ventral (prospective epidermal) ectoderm. The expression of GoLI is therefore related to the state of competence of the tissue rather than to its fate. At the early neurula stage, immediately following neural induction, the expression of GoLI persists essentially in that part of ectoderm that has been diverted from epidermal differentiation towards the neural pathway; in the ventral ectoderm, as neural competence is lost GoLI disappears. Furthermore, in the neurectoderm, only approximately 70% of the cells conserve GoLI, demonstrating that immediately following neural induction the population of neurectodermal cells is not homogeneous.

Animals↗

PubMed2005

Neural mechanisms underlying the processing of Chinese words: an fMRI study.

The present study employed functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms underlying orthographic, phonological and semantic processing of single character Chinese words. Twelve right-handed native Chinese speakers participated in the study. Three fundamental linguistic tasks including orthographic judgment, phonological matching and semantic association task were used. Our results demonstrated robust activation in the left posterior inferior temporal cortex (BA 37) for all three tasks. While the phonological matching task produced left-lateralized activation in the inferior frontal and parietal regions, semantic association task showed considerable bilateral activation in the inferior frontal and occipito-parietal regions. Direct comparison between phonological matching and semantic association task yielded semantic related activation in the anterior portion of the left inferior frontal gyrus (BA 47) and the right inferior frontal region (Broca's homology; BA 45). Behaviorally, there was no difference in response time between phonological matching and semantic association task. Our findings suggested that differential neural pathways were involved in the processing of meaning and sound of single-character Chinese words. The present study provided systemic information of the neural substrates underlying the processing of different components of Chinese language.

Adult↗

PubMed1985

Reduced anesthetic requirement after electrical stimulation of periaqueductal gray matter.

To determine whether electrical stimulation of the periaqueductal gray region decreases anesthetic requirement, the authors studied the effect of such stimulation on the MAC of halothane and 60% nitrous oxide in 33 patients. These patients, who were undergoing implantation of a radio-frequency-coupled receiver and connection of that receiver to electrodes previously implanted in the periaqueductal gray area, were assigned randomly to receive (n = 16) or not receive (n = 17) electrical stimulation 1 h before surgery. The mean value (+/- SEM) for the minimum alveolar concentration of halothane combined with 60% nitrous oxide was significantly less (P less than 0.001) for patients who were stimulated preoperatively (0.15 +/- 0.05%) than for those who were not (0.51 +/- 0.02%). The authors conclude that stimulation of the periaqueductal gray region decreases anesthetic requirements and believe that at least three mechanisms are possible: a nonspecific narcotic-like effect, a specific effect on a pain pathway, or an effect on specific neural pathways that affect anesthetic requirements secondary to changes in regional concentrations of neurotransmitters.

Anesthesia, Inhalation↗

PubMed2006

Influence of motilin on gastric fundus tone and on meal-induced satiety in man: role of cholinergic pathways.

BACKGROUND: Motilin agonists are strong gastroprokinetics, but their impact on symptoms in delayed gastric emptying has been disappointing. It has been speculated that it is due to the contractile effect of motilin agonists on the proximal stomach, but the pathway involved and the symptomatic consequences have been incompletely elucidated. AIMS: To study whether motilin enhances proximal stomach tone and enhances meal-induced satiety and to evaluate whether this effect involves a cholinergic pathway. METHODS: A gastric barostat was used to study, in healthy subjects, the effect of motilin (300 ng/kg/30 min i.v.) or saline on fasting gastric fundus tone and on post-prandial relaxation. To evaluate the involvement of a cholinergic pathway, atropine (12 microg/kg/h) was administered intravenously simultaneously with or before and during motilin infusion in the fasting state. Finally, a satiety drinking test was performed in 21 subjects twice after pretreatment with placebo or motilin and with placebo or atropine. RESULTS: Administration of motilin caused a significant increase of fasting fundus tone expressed as decrease of the mean balloon volume (324 +/- 60 mL vs 213 +/- 62 mL, p < 0.05). Simultaneous administration of atropine and motilin did not generate a significant volume change (192 +/- 60 mL vs 181 +/- 83 mL, NS), but pretreatment with atropine alone induced a relaxation, and when motilin was added this revealed an ongoing contraction (192 +/- 24 mL vs 136 +/- 21 mL, p < or = 0.05). Motilin infusion also inhibited gastric accommodation (p < or = 0.05 vs placebo) and increased satiety during a satiety drinking test (p < or = 0.05 vs placebo). CONCLUSIONS: Administration of motilin causes a contraction of the proximal stomach in humans and increases meal-induced satiety. The effect of motilin is atropine-resistant and involves a direct muscular pathway or a non-cholinergic neural pathway.

Adult↗

PubMed1982

Effects of left atrial stretch in cardiac-denervated and intact conscious dogs.

We monitored cardiovascular and renal function in conscious dogs with surgically denervated hearts during two experimental procedures: 1) inflation of a balloon in the left atrium and 2) intravascular volume expansion. The results obtained were compared with results from identical experiments on sham-operated control dogs. Left atrial balloon inflation in the sham-operated dogs produced an increase in left atrial pressure, heart rate, urine flow, and sodium excretion; central venous pressure decreased. These changes were absent in the cardiac-denervated dogs. Infusion of 6% dextran in isotonic saline (16% of estimated blood volume) increased the heart rate significantly in the control dogs but not in the cardiac-denervated dogs; other hemodynamic measurements were comparable in the two groups. Urine flow and sodium excretion increased significantly in both the cardiac-denervated and control dogs; the responses did not differ significantly between the two groups. These experiments demonstrate that inflation of a balloon in the left atrium of a conscious dog elicits diuretic and natriuretic responses that are dependent on intact cardiac neural pathways, presumably specifically dependent on afferent neural impulses from left atrial receptors. On the other hand, an increase in circulating blood volume induced by the intravenous infusion of an isotonic, isoncotic solution elicits diuretic and natriuretic responses in the cardiac-denervated dog that are similar to the renal responses produced in a control dog. Thus, although cardiac receptors are capable of eliciting reflex changes in both hemodynamics and renal function, it is not clear what role they play in mediating the renal responses evoked by increases in blood volume.

Animals↗

PubMed2000

Developmental changes in eye-blink conditioning and neuronal activity in the cerebellar interpositus nucleus.

Neuronal activity was recorded in the cerebellar interpositus nucleus in infant rats during classical conditioning of the eye-blink response. The percentage and amplitude of eye-blink conditioned responses increased as a function of postnatal age. Learning-specific neuronal activity in the cerebellum emerged ontogenetically in parallel with the eye-blink conditioned response. There were also age-specific changes in neuronal activity after the onset of the conditioned and unconditioned stimuli. The results indicate that the development of the eye-blink conditioned response may depend on the development of stimulus-evoked neuronal responses and learning-specific plasticity in the cerebellum. Functional immaturity in the afferent neural pathways may limit the induction of neural plasticity in the cerebellum and thereby limit the development of the eye-blink conditioned response.

Acoustic Stimulation↗

PubMed1985

Genetic suppression of putative guidepost cells: effect on establishment of nerve pathways in Drosophila wings.

In the developing wing of Drosophila a set of early differentiating neurons pioneer the axon courses observed in the adult. The possibility that these first cells are indispensable for establishing the normal neural pathways has been tested. The differentiation of particular neurons was suppressed by inducing cell clones homozygous for two scute deficiencies, mutations that inhibit the differentiation of sensilla and their associated neurons. From the analysis of the nerve patterns in wings lacking specific sensilla, it has been demonstrated that none of the identified neurons are essential for guiding other axons along the correct path. However, the possibility remains that the presence of certain cells may increase the probability of establishing the normal pattern of peripheral nerves.

Animals↗

PubMed1977

Hyperphagia and obesity produced by parasagittal and coronal hypothalamic knife cuts: further evidence for a longitudinal feeding inhibitory pathway.

Hyperphagia and obesity are produced both by parasagittal knife cuts through the medial hypothalamus and by coronal knife cuts through the posterior hypothalamus. The results of this study indicate that the two types of cuts produce their overeating effect by severing the same neural pathway. Experiment 1 demonstrated that unilateral parasagittal knife cuts combined with contralateral coronal cuts in either the posterior hypothalamus or the midbrain significantly increase food intake and body weight. Experiment 2 revealed that bilateral parasagittal cuts and bilateral coronal cuts in the hypothalamus produce qualitatively similar effects on food intake, diurnal ingestive pattern, finickiness, and amphetamine anorexia. The two types of cuts differentially altered water intake, however. In Experiment 3, coronal cuts in the posterior hypothalamus, like parasagittal cuts in the medial hypothalamus, were found to increase the food intake and body weight of rats previously given bilateral parasagittal transections through the lateral perifornical region. The neuroanatomy and neurochemistry of the longitudinal feeding inhibitory pathway suggested by these results are discussed.

Amphetamine↗

PubMed2005

Movement control: dedicated or distributed?

Neural networks in which 'commands' spread 'horizontally' across multiple neurons have been believed to mediate motor pattern variation. A recent study shows that dedicated 'vertical' neural pathways can also underlie these variations.

Animals↗

PubMed1998

Evidence for global motion interactions between first-order and second-order stimuli.

Recent research indicates that the early stages of visual-motion analysis involve two parallel neural pathways, one conveying information from luminance-defined (first-order) image features, the other conveying information from texture-defined (second-order) features. It is still not clear whether these two pathways converge during later stages of global motion integration. According to one account they remain segregated, and feed separate global analyses. In the alternative account, all responses feed a common stage of global analysis. Two perceptual phenomena are universally held to result from interactions between detector responses during global motion integration--direction repulsion and motion capture. We conducted two psychophysical experiments on these phenomena to test for segregation of first-order and second-order responses during integration. Stimuli contained two components, either two random-block patterns transparently drifting in different directions (repulsion measurements), or a drifting square-wave grating superimposed on an incoherent random-block pattern (capture measurements). Repulsion and capture effects were measured when both stimulus components were the same order, and when one component was first order and the other was second order. Both effects were obtained for all combinations of first-order and second-order patterns. Repulsion effects were stronger with first-order inducing patterns, and capture effects were stronger with second-order inducers. The presence of perceptual interactions regardless of stimulus order strongly suggests that responses in first-order and second-order pathways interact during global motion analysis.

Computer Graphics↗

PubMed1999

An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems.

BACKGROUND: The goal of this study was to model the functional connectivity of the neural systems that subserve attention and impulse control. Proper performance of the Stroop Word-Color Interference Task requires both attention and impulse control. METHODS: Word-color interference was studied in 34 normal adult subjects using functional magnetic resonance imaging. RESULTS: Interregional correlation analyses suggested that the anterior cingulate is coupled functionally with multiple regions throughout the cerebrum. A factor analysis of the significant regional activations further emphasized this functional coupling. The cingulate or related mesial frontal cortices loaded on each of the seven factors identified in the factor analysis. Other regions that loaded significantly on these factors have been described previously as belonging to anatomically connected circuits believed to subserve sensory tuning, receptive language, vigilance, working memory, response selection, motor planning, and motor response functions. These seven factors appeared to be oriented topographically within the anterior cingulate, with sensory, working memory, and vigilance functions positioned more rostrally, and response selection, motor planning, and motor response positioned progressively more caudally. CONCLUSIONS: These findings support a parallel distributed processing model for word-color interference in which portions of the anterior cingulate cortex modify the strengths of multiple neural pathways used to read and name colors. Allocation of attentional resources is thought to modify pathway strengths by reducing cross-talk between information processing modules that subserve the competing demands of reading and color naming. The functional topography of these neural systems observed within the cingulate argues for the presence of multiple attentional subsystems, each contributing to improved task performance. The topography also suggests a role for the cingulate in coordinating and integrating the activity of these multiple attentional subsystems.

Adolescent↗

PubMed1999

Neuronal activity during development: permissive or instructive?

Experimental studies over the past year have shown that neural activity has a range of effects on the development of neural pathways. Although activity appears unimportant for establishing many aspects of the gross morphology and topology of the brain, there are many cases where the presence of neural activity is essential for the formation of a mature system of neural connections; in some instances, the pattern of neural activity actually orchestrates the final arrangement of neural connections.

Amphibians↗

PubMed1978

Autoradiographic evidence for pathways from the medial preoptic area to the midbrain involved in the drinking response to angiotensin II.

The 3H-amino acid autoradiographic method was used to localize intracerebral sites from which angiotensin II (AII) elicits drinking and to identify their efferent neural pathways. Small injections (0.02-0.1 mul) of AII and 3H-amino acid mixtures were injected together or separately into widespread regions of the forebrain of adult rats in normal food and water balance. From an analysis of 39 positive and negative injection sites it was concluded that the caudal half of the medial preoptic area and the adjacent rostral part of the anterior hypothalamic area are sensitive to AII. Two anatomically defined pathways arising from neurons within this region were identified. One descends through the medial forebrain bundle and appears to terminate in the lateral hypothalamic area, the ventromedial nucleus, the mammillary body, and the ventral tegmental area. The other descends through the periventricular region and posterior hypothalamic area to end in the midbrain central gray. Additional widespread connections with the amygdala, septum, habenula, and pons appear to arise in the lateral preoptic area (Swanson, '76). Combined AII-3H-amino acid injections centered in the subfornical organ only elicited drinking in those cases in which injected label diffuse through the third ventricle to the medial preoptic area. No efferent pathways were identified in experiments in which a small injection (0.02 mul) heavily labeled cells strictly confined to the subfornical organ and there was no ventricular spread of label.

Angiotensin II↗