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PubMed2000

Central nervous system structures connected with the endocrine glands. findings obtained with the viral transneuronal tracing technique.

This review is a summary of recent neuromorphological observations on the existence of multisynaptic neural pathways between the endocrine glands and the central nervous system (CNS) and its structures involved in this pathway. Introduction of the viral transneuronal tracing technique has made possible investigations of multisynaptic connections. The utility of this approach is based on the ability of the neurotropic virus to invade and replicate in neurons, and then gradually infect synaptically linked second-order, third-order. etc. neurons. Injecting the virus into the endocrine glands, this technique was used to identify cell groups in the spinal cord and in the brain which are connected with the adrenal gland, the gonads and the pancreas. Injection of the virus into these organs resulted in viral labeling of neurons in practically identical structures of the CNS including the intermediolateral cell column of the spinal cord, the vagal nuclei and certain other cell groups in the brain stem. In the hypothalamus the most intensive labeling was in the parvocellular part of the paraventricular nucleus and in the telencephalon labeled nerve cells were detected in the amygdala, the bed nucleus of the stria terminalis and in the preoptic area. It is known that the labeled CNS structures are members of descending pathways arising from the hypothalamic paraventricular nucleus or from other cell groups and terminating on neurons of the vagal nuclei and the intermediolateral cell column of the spinal cord. Experimental data support the view that the CNS structures and pathways connected with the endocrine glands are involved in the neural control of these organs.

Animals↗

PubMed2000

Speech-like cerebral activity in profoundly deaf people processing signed languages: implications for the neural basis of human language.

For more than a century we have understood that our brain's left hemisphere is the primary site for processing language, yet why this is so has remained more elusive. Using positron emission tomography, we report cerebral blood flow activity in profoundly deaf signers processing specific aspects of sign language in key brain sites widely assumed to be unimodal speech or sound processing areas: the left inferior frontal cortex when signers produced meaningful signs, and the planum temporale bilaterally when they viewed signs or meaningless parts of signs (sign-phonetic and syllabic units). Contrary to prevailing wisdom, the planum temporale may not be exclusively dedicated to processing speech sounds, but may be specialized for processing more abstract properties essential to language that can engage multiple modalities. We hypothesize that the neural tissue involved in language processing may not be prespecified exclusively by sensory modality (such as sound) but may entail polymodal neural tissue that has evolved unique sensitivity to aspects of the patterning of natural language. Such neural specialization for aspects of language patterning appears to be neurally unmodifiable in so far as languages with radically different sensory modalities such as speech and sign are processed at similar brain sites, while, at the same time, the neural pathways for expressing and perceiving natural language appear to be neurally highly modifiable.

Cerebrovascular Circulation↗

PubMed2002

Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: comparison with scratching behavior.

Scratching behavior is used to assess itch sensation in animals, but few studies have addressed the relative scratch-inducing capacity of different algesic and pruritic chemicals. Furthermore, central neural mechanisms underlying itch are not well understood. We used electrophysiological and behavioral methods to investigate the ability of several irritant chemicals to excite neurons in the superficial dorsal horn, as well as to elicit scratching, in rats. In anesthetized rats, single neurons in the superficial lumbar dorsal horn, identified by their responsiveness to intracutaneous (ic) histamine, were classified as wide dynamic range (WDR) or nociceptive-specific (NS). Serotonin (5-HT) given ic to the paw excited most (88%) WDR and NS neurons over a prolonged time course (often up to 40 min). 5-HT-evoked responses exhibited significant tachyphylaxis. Most neurons also gave shorter-duration responses to ic capsaicin (92%) and mustard oil (71%). In separate behavioral experiments, significant dose-related hind limb scratching directed at the ic injection site in the back of the neck was elicited by 5-HT over a time course similar to that of evoked neuronal firing. A second 5-HT injection made 40 min later at the same site elicited significantly less scratching. Formalin also elicited scratching that was not dose-related and less than that evoked by 5-HT. 5-HT and Formalin also evoked head or whole-body shakes that were significantly correlated with scratching. Neither histamine, capsaicin, nor vehicle controls elicited significant scratching or shaking. In rats, 5-HT appears to be more pruritogenic than histamine as assessed by scratching and shaking behavior, and excites superficial dorsal horn neurons over a behaviorally relevant time course. However, because most neurons additionally responded to pain-producing stimuli, they are not itch-specific. They might nonetheless contribute to neural pathways that distinguish between pain and itch based on some neural mechanism such as frequency coding.

Animals↗

PubMed1998

Angiotensin, thirst, and sodium appetite.

Angiotensin (ANG) II is a powerful and phylogenetically widespread stimulus to thirst and sodium appetite. When it is injected directly into sensitive areas of the brain, it causes an immediate increase in water intake followed by a slower increase in NaCl intake. Drinking is vigorous, highly motivated, and rapidly completed. The amounts of water taken within 15 min or so of injection can exceed what the animal would spontaneously drink in the course of its normal activities over 24 h. The increase in NaCl intake is slower in onset, more persistent, and affected by experience. Increases in circulating ANG II have similar effects on drinking, although these may be partly obscured by accompanying rises in blood pressure. The circumventricular organs, median preoptic nucleus, and tissue surrounding the anteroventral third ventricle in the lamina terminalis (AV3V region) provide the neuroanatomic focus for thirst, sodium appetite, and cardiovascular control, making extensive connections with the hypothalamus, limbic system, and brain stem. The AV3V region is well provided with angiotensinergic nerve endings and angiotensin AT1 receptors, the receptor type responsible for acute responses to ANG II, and it responds vigorously to the dipsogenic action of ANG II. The nucleus tractus solitarius and other structures in the brain stem form part of a negative-feedback system for blood volume control, responding to baroreceptor and volume receptor information from the circulation and sending ascending noradrenergic and other projections to the AV3V region. The subfornical organ, organum vasculosum of the lamina terminalis and area postrema contain ANG II-sensitive receptors that allow circulating ANG II to interact with central nervous structures involved in hypovolemic thirst and sodium appetite and blood pressure control. Angiotensin peptides generated inside the blood-brain barrier may act as conventional neurotransmitters or, in view of the many instances of anatomic separation between sites of production and receptors, they may act as paracrine agents at a distance from their point of release. An attractive speculation is that some are responsible for long-term changes in neuronal organization, especially of sodium appetite. Anatomic mismatches between sites of production and receptors are less evident in limbic and brain stem structures responsible for body fluid homeostasis and blood pressure control. Limbic structures are rich in other neuroactive peptides, some of which have powerful effects on drinking, and they and many of the classical nonpeptide neurotransmitters may interact with ANG II to augment or inhibit drinking behavior. Because ANG II immunoreactivity and binding are so widely distributed in the central nervous system, brain ANG II is unlikely to have a role as circumscribed as that of circulating ANG II. Angiotensin peptides generated from brain precursors may also be involved in functions that have little immediate effect on body fluid homeostasis and blood pressure control, such as cell differentiation, regeneration and remodeling, or learning and memory. Analysis of the mechanisms of increased drinking caused by drugs and experimental procedures that activate the renal renin-angiotensin system, and clinical conditions in which renal renin secretion is increased, have provided evidence that endogenously released renal renin can generate enough circulating ANG II to stimulate drinking. But it is also certain that other mechanisms of thirst and sodium appetite still operate when the effects of circulating ANG II are blocked or absent, although it is not known whether this is also true for angiotensin peptides formed in the brain. Whether ANG II should be regarded primarily as a hormone released in hypovolemia helping to defend the blood volume, a neurotransmitter or paracrine agent with a privileged role in the neural pathways for thirst and sodium appetite of all kinds, a neural organizer especially in sodium appetit

Angiotensin II↗

PubMedDate not supplied

Circadian disorganization in experimental arthritis.

This review discusses the experimental evidence indicating that arthritis disrupts circadian organization, which was mainly derived from animal studies employing Freund's complete mycobacterial adjuvant (FCA). The defense response to antigenic challenge, mediated in part by cytokines, includes changes in chronobiological central nervous system function, like depressed daily activity, superficial sleep or anorexia. Interferon (IFN)-gamma receptors are detectable in the central circadian pacemaker, the hypothalamic suprachiasmatic nuclei, at a time when the capacity for photic entrainment of the pacemaker became established. The disruptive effects of the systemic injection of IFN on the circadian rhythms of locomotor activity, body temperature and clock-gene mRNA expression have been documented. In the last few years we have examined a number of immune and neuroendocrine circadian rhythms in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-hour organization of immune and neuroendocrine responses becomes altered. A hormonal pathway involving the circadian secretion of melatonin and a purely neural pathway including, as a motor leg, the autonomic nervous system innervating the lymph nodes were identified. The significant effects of the immune-mediated inflammatory response on the diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented the alteration in 24-hour rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin pretreatment prevented the alteration in the 24-hour variation in hypothalamic serotonin and dopamine turnover during the preclinical phase of Freund's adjuvant arthritis in rats. Some pinealectomy-induced immune changes in arthritic rats were also prevented by physiological concentrations of melatonin. Melatonin may play the role of an 'internal synchronizer' for the immune system.

Animals↗

PubMed1993

Different central areas involved in the mechanisms of morphine antinociception in the mouse and the rat.

The antinociceptive effect of morphine quantitated by the tail-flick (TF) response was studied in mice and rats with various preparations, including: precollicular transection, partial and complete anemic decerebration, vertebral artery infusion, cross-circulation, spinal ligation, spinalization with dura mater intact and spinal subarachnoid infusion. In mice, either precollicular transection or partial anemic decerebration abolished or greatly reduced the morphine antinociceptive action (MAA). However, in rats, neither precollicular transection nor complete anemic decerebration caused any significant reduction in MAA. Studies of vertebral artery infusion and cross-circulation in both species indicated that opiate-sensitive antinociceptive receptors (OSAR) were present in the hindbrain. Although, spinal ligation eliminated MAA in both species, spinalization with dura mater intact only abolished the MAA in rats. On the other hand, studies of spinal subarachnoid infusion showed that only spinal antinociceptive neurons of mice were highly sensitive to the enzyme-resistant enkephalin (Enk) analog. From all these results suggested that both pre- and post-collicular structures are necessary for MAA in the mouse, however, in the rat only the post-collicular structures are essential, furthermore, the humoral pathway seems to play a more important role than the neural pathway in the inhibition of the TF response in the mouse but just the opposite in the rat. Therefore, it is concluded that the mechanisms of MAA are different between the mouse and the rat. The possible mechanisms of MAA in both species were discussed.

Analgesia↗

PubMed1983

The regulation of cardiovascular functions by monoamine neurotransmitters in the brain.

The complexity of the central nervous system's influence on cardiovascular integration is underscored by the extensive neural interconnections between the various higher and lower brain structures shown by electrophysiological studies to have an influence on cardiovascular function. Furthermore, complex neural connections exist within each level of cardiovascular integration (for instance, the medullary reticular formation, or the limbic system). The electrophysiological analysis of the integrative aspects of central cardiovascular regulation has been the subject of several reviews (Reis, 1972; Smith, 1974; Calaresu et al., 1975; Oberg, 1976). In recent years, the methodology of analyzing the anatomical neural pathways of central cardiovascular regulation by lesion-degeneration, evoked potential, and fluorescent histochemical procedures, has been improved with the introduction of anterograde and retrograde tracer techniques. The result is the delineation of previously undetected neural interconnections among various brain areas, long known as cardiovascular centres, such as the NTS, the parabrachial nucleus, the paraventricular nucleus of the hypothalamus, the central nucleus of the amygdala, and the bed nucleus of the stria terminalis (Loewy & McKellar, 1980). Undoubtedly the next few years will see major advances in the understanding of the neuroanatomical pathways involved in central cardiovascular control.

Animals↗

PubMed1992

Reticular formation influences on primary and non-primary auditory pathways as reflected by the middle latency response.

Ongoing studies are aimed at identifying the neural pathways responsible for the middle latency response (MLR). These studies involve the analysis of surface and intracranial potentials following pharmacologic inactivation (with lidocaine) of discrete regions of the guinea pig brain. Previous investigations have shown that MLR surface waves recorded over the temporal lobe originate from pathways anatomically and functionally distinct from those that generate MLR waves recorded over the midline, and that both primary and non-primary auditory thalamo-cortical pathways contribute to the guinea pig MLR. The present investigation examines the role of the mesencephalic reticular formation (mRF) in the MLR generating system. Inactivation of the mRF was associated with disruption of the midline response. These waves have been shown to reflect activity from non-primary subdivisions of the thalamo-cortical pathway. Components recorded over the temporal lobe were also affected, consisting of amplitude reduction and latency prolongation without changes in response morphology. Changes in temporal MLR components with mRF inactivation were smaller than those associated with direct inactivation of primary and non-primary subdivisions of the medial geniculate body. These findings indicate that mRF input is essential for normal generation of those components of the MLR thought to reflect both primary and non-primary auditory pathway activity.

Animals↗

PubMed2002

Upright posture reduces thermogenesis and augments core hypothermia.

UNLABELLED: We recently reported that baroreceptor-mediated reflexes modulate thermoregulatory vasoconstriction during lower abdominal surgery. Accordingly, we examined the hypothesis that postural differences and the related alterations in baroreceptor loading similarly modulate the thermogenic (i.e., shivering) response to hypothermia in humans. In healthy humans (n = 7), cold saline was infused IV (30 mL/kg at 4 degrees C) for 30 min to decrease core temperature. Each participant was studied on 2 separate days, once lying supine and once sitting upright. Tympanic membrane temperature and oxygen consumption were monitored for 40 min after each saline infusion. The decrease in core temperature upon completion of the infusion in the upright posture position was 1.24 degrees C +/- 0.07 degrees C, which was significantly greater than the 1.02 degrees C +/- 0.06 degrees C seen in the supine position. The core temperature was reduced by 0.59 degrees C +/- 0.07 degrees C in the upright position but only by 0.37 degrees C +/- 0.05 degrees C in the supine position when the increase in oxygen consumption signaling thermogenic shivering occurred. Thus, the threshold temperature for thermogenesis was significantly less in the upright than the supine position. The gain of the thermogenic response did not differ significantly between the positions (363 +/- 69 mL. min(-1). degrees C(-1) for upright and 480 +/- 80 mL. min(-1). degrees C(-1) for supine). The skin temperature gradient was significantly larger in the upright than in the supine posture, suggesting that the peripheral vasoconstriction was augmented by upright posture. Plasma norepinephrine concentrations increased in response to cold saline infusion under both conditions, but the increase was significantly larger in the upright than in the supine posture. Baroreceptor unloading thus augments the peripheral vasoconstrictor and catecholamine response to core hypothermia but simultaneously reduces thermogenesis, which consequently aggravated the core temperature decrease in the upright posture. IMPLICATIONS: Upright posture attenuates the thermogenic response to core hypothermia but augments peripheral vasoconstriction. This divergent result suggests that input from the baroreceptor modifies the individual thermoregulatory efferent pathway at a site distal to the common thermoregulatory center or neural pathway.

Adult↗

PubMed1997

Unilateral sensori-neural hearing disturbance caused by intramedullary cerebellar tumors--three case reports.

Three patients presented with unilateral sensori-neural hearing disturbance as the initial symptom of cerebellar tumors: a 19-year-old female with a medulloblastoma (Case 1), a 45-year-old male with a cerebellar low-grade glioma (Case 2), and a 49-year-old female with a cerebellaer hemangioblastoma (Case 3). In Cases 1 and 2, the whole length of the eight cranial nerve was intact according to magnetic resonance imaging and intraoperative findings. In Case 3, the intracerebellar tumor had bulged into the cerebellopontine cistern, compressing the eighth cranial nerve near the brainstem. Auditory evoked brainstem responses showed only the first wave in all three patients, and the following waves could not be discriminated. Unilateral sensori-neural hearing disturbance occurs very rarely in patients with intramedullary cerebellar lesions because the auditory neural pathway is bilaterally innervated. Intramedullary tumors may cause unilateral sensori-neural hearing disturbance by infiltrating or causing edematous changes of the eighth cranial nerve or the cochlear nucleus in the brainstem, or by compressing the nerve in the cistern. The symptoms are the same as those of acoustic neurinoma, so intramedullary cerebellar tumors should be considered in the differential diagnosis of unilateral sensorineural hearing disturbance.

Adult↗

PubMed2004

Irritable bowel syndrome: a model of the brain-gut interactions.

Brain-gut interactions are increasingly recognized as underlying pathomechanisms of functional gastrointestinal disorders. Bi-directional communication between the central nervous system (CNS) and the enteric nervous system (ENS) occurs both in health and disease. Various CNS- and gut-directed stressors stimulate the brain-gut axis. Processes modulating responsiveness to stressors along the brain-gut axis involve neural pathways, the immunological, and endocrinological mechanisms. Disturbances at every level of neural control of the gastrointestinal tract can affect modulation of gastrointestinal motility, secretion, immune functions as well as perception and emotional response to visceral events. ENS function, central processing, and autonomic regulation play an important role in the brain-gut dialogue. Stress and emotions may trigger neuroimmune and neuroendocrine reactions via the brain-gut axis. Various non-site specific neurotransmitters influence gastrointestinal, endocrine and immune function, as well as human behavior and emotional state, depending on their location. The physiology of the digestive tract, the subjective experience of symptom, health behavior, and treatment outcome are strongly affected by psychosocial factors. Recently, a biopsychosocial model of IBS containing physiological, emotional, cognitive and behavioral components has been proposed. Rapid progress in neurogastroenterology, using new brain imaging techniques, should bring better understanding of the brain-gut axis and open new therapeutic perspectives.

Brain↗

PubMed2005

Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems.

Effective perception of fear signals is crucial for human survival and the importance of the amygdala in this process is well documented. Animal, lesion and neuroimaging studies indicate that incoming sensory signals of fear travel from thalamus to amygdala via two neural pathways: a direct subcortical route and an indirect pathway via the sensory cortex. Other lines of research have demonstrated prefrontal modulation of the amygdala. However, no study to date has examined the prefrontal modulation of the thalamo-cortico-amygdala pathways in vivo. We used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamus, amygdala and sensory (inferior occipital, fusiform) cortices, and the modulation of these networks by the anterior cingulate cortex (ACC). Functional magnetic resonance imaging (fMRI) data were acquired for 28 healthy control subjects during a fear perception task, with neutral as the 'baseline' control condition. Main effect analysis, using a region of interest (ROI) approach, confirmed that these regions are part of a distributed neural system for fear perception. Psychophysiological interactions revealed an inverse functional connectivity between occipito-temporal visual regions and the left amygdala, but a positive connectivity between these visual region and the right amygdala, suggesting that there is a hemispheric specialization in the transfer of fear signals from sensory cortices to amygdala. Physiophysiological interactions revealed a dorsal-ventral division in ACC modulation of the thalamus-sensory cortex pathway. While the dorsal ACC showed a positive modulation of this pathway, the ventral ACC exhibited an inverse relationship. In addition, both the dorsal and ventral ACC showed an inverse interaction with the direct thalamus-amygdala pathway. These findings suggest that thalamo-amygdala and cortical regions are involved in a dynamic interplay, with functional differentiation in both lateralized and ventral/dorsal gradients. Breakdowns in these interactions may give rise to affect-related symptoms seen in a range of neuropsychiatric disorders.

Adult↗

PubMed1988

[Lesions of the posterior visual pathways: clinical presentation and mechanisms of functional restoration].

The present paper begins with a brief discussion of general clinical features found in patients with lesions of the posterior visual pathways. The author goes on to discuss various mechanisms of restitution of function in the central nervous system, including activation of neural pathways subserved by spared neurons, metabolic modulations, and neural plasticity.

Brain Damage, Chronic↗

PubMed2002

Serotonin sets the day state in the neurons that control coupling between the optic lobe circadian pacemakers in the cricket Gryllus bimaculatus.

The bilaterally paired optic lobe circadian pacemakers of the cricket Gryllus bimaculatus mutually exchange photic and circadian information to keep their activity synchronized. The information is mediated by a neural pathway, consisting of the so-called medulla bilateral neurons, connecting the medulla areas of the two optic lobes. We investigated the effects of serotonin on the neural activity in this coupling pathway. Spontaneous and light-induced electrical activity of the neurons in the coupling pathway showed daily variations, being more intense during the night than the day. Microinjection of serotonin or a serotonin-receptor agonist, quipazine, into the optic lobe caused a dose- and time-dependent inhibition of spontaneous and light-induced responses, mimicking the day state. The amount of suppression was greater and the recovery from the suppression occurred faster during the night. Application of metergoline, a non-selective serotonin-receptor antagonist, increased spontaneous activity and light-evoked responses during both the day and the night, with higher effect during the day. In addition, metergoline effectively attenuated the effects of serotonin. These facts suggest that in the cricket's optic lobe, serotonin is released during the daytime and sets the day state in the neurons regulating coupling between the bilaterally paired optic lobe circadian pacemakers.

Animals↗

PubMed1985

Modifications of adrenocortical responses following frontal cortex simulation in rats with hypothalamic deafferentations and medial forebrain bundle lesions.

With the purpose of delineating the neural pathways in the rat which mediate adrenocortical responses following frontal cortex stimulation, the effects of partial hypothalamic deafferentations and medial forebrain bundle lesion were studied. In intact and sham-operated animals, cortical stimulation through permanently implanted electrodes caused a significant increase in plasma corticosterone levels. In rats with anterior hypothalamic deafferentation and bilateral medial forebrain bundle lesions the adrenal response to cortical stimulation was blocked completely, while in animals with posterior hypothalamic deafferentation there occurred a normal rise in plasma corticosterone. These studies demonstrate that the frontal cortex effects on adrenocortical secretion are neurally mediated and involve an anterior hypothalamic input, more specifically the medial forebrain bundle.

Adrenal Cortex↗

PubMed1983

Neutral red stains ganglia in the vagal motor pathway to ferret trachea without affecting ganglionic transmission.

To determine the effect of Neutral red (0.01%) on neural transmission through ganglia, we used an in vitro nerve-muscle preparation of ferret trachea. Before, during, and after incubating the trachea in Neutral red, we induced isometric muscle contractions first by activating preganglionic fibers with electrical stimulation of the vagus nerve, and then by activating postganglionic nerve fibers with electrical field stimulation. Incubation in Neutral red (0.01%) for 45 min at 38 degrees C reduced the responses to both pre- and postganglionic activation. When the control responses to pre- and postganglionic activation were matched. Neutral red depressed the 2 responses to the same degree, implying that the depression was confined to postganglionic structures. Washout of Neutral red from the medium restored the responses to both pre- and postganglionic activation. Histologic examination of all tissues proved that the ganglia were still stained after the washout procedure. We conclude that Neutral red (0.01%) depresses smooth muscle contractions evoked through neural pathways, and that this depression is reversible and confined to postganglionic structures, leaving ganglionic transmission intact.

Animals↗

PubMed1995

Cholinergic and VIP-ergic pathways mediate histamine H2 receptor-induced cyclical secretion in the guinea pig colon.

Previous studies demonstrated neurally mediated recurrent increases in short-circuit current (Isc) suggestive of anion secretion in guinea pig distal colon. To determine the neural pathways involved, segments of distal colon from guinea pigs were mounted in flux chambers. In muscle-stripped or whole thickness preparations, serosal addition of the histamine H2 receptor agonist, dimaprit, caused cyclical increases in Isc, which were reduced by the chloride channel blocker, N-phenylanthranilic acid, but not by the sodium channel blocker amiloride. Dimaprit stimulated release of [3H]acetylcholine and vasoactive intestinal polypeptide (VIP) from submucosal/mucosal sheets. Dimaprit caused recurrent increases in Isc, which were significantly decreased by mecamylamine, a nicotinic receptor antagonist, and nearly abolished by the muscarinic antagonist, atropine (M3 > M1 = M2). The muscarinic antagonist, 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, M3 > M1), was more potent than pirenzepine (M1 > M3) in reducing recurrent increases in Isc. Dimaprit- and electrically evoked secretion were inhibited by the VIP antagonists [4Cl-D-Phe6, Leu17]VIP and VIP hybrid. The results suggest the involvement of VIP-ergic and cholinergic neurons utilizing nicotinic and muscarinic synapses in mediating secretion.

Acetylcholine↗

PubMed1987

Pathogenesis of scrapie is faster when infection is intraspinal instead of intracerebral.

Previous studies of mice infected peripherally with 139A scrapie showed that scrapie agent initially replicates outside the CNS and that invasion of the CNS occurs several weeks later by neural spread of infection along visceral autonomic fibres to the mid-thoracic cord, and thence to brain. Direct intracerebral infection of brain bypasses the need for extraneural replication and gives shorter incubation periods than peripheral routes. However, it was also found that the duration of the scrapie replication phase in brain, before clinical disease develops, is actually shorter with peripheral routes than with the intracerebral route. We have now investigated this surprising observation using the intraspinal route to reproduce just the neural phase of scrapie pathogenesis seen after peripheral infection. In studies of three strains of scrapie (263K, 139A and ME7) in either hamsters or mice, we have fulfilled the prediction that incubation periods should be shorter after intraspinal infection than after intracerebral infection. Detailed studies of 139A scrapie showed that the shorter incubation period by the intraspinal route could be accounted for by the shorter duration of the scrapie replication phase in brain before clinical disease developed. As a consequence, the severity of the vacuolar lesions in brain at the clinical stage of all three scrapie models was less after intraspinal infection than after intracerebral infection but the severities of vacuolation after intraspinal and intraperitoneal infection were remarkably similar. We speculate that (a) the site of injection (or of invasion) of the central nervous system determines which neural pathways become accessible for the spread of scrapie infection, and that (b) the duration of the neural phase of scrapie pathogenesis is related to the complexity of the pathways between the site of invasion and the clinical target areas in which, it is suggested, scrapie must replicate for disease to develop.

Animals↗