PubMed Health⌕ Search

Biomedical subjects

J F Lorden

Publications and source records attributed to J F Lorden.

At least 19 recordsLinked to original sources
PubMed1999

Psychoneuroendocrine immunology: perception of stress can alter body temperature and natural killer cell activity.

Psychoimmunology has been credited with using the mind as a way to alter immunity. The problem with this concept is that many of the current psychoimmunology techniques in use are aimed at alleviating stress effects on the immune system rather than at direct augmentation of immunity by the brain. Studies in animals provide a model that permits us to approach the difficulties associated with gaining an understanding of the CNS-immune system connection. A particular advantage of using animals over humans is that psychological and social contributions play a less prominent role for animals than for human subjects, since the animals are all inbred and reared under identical controlled conditions. If the insightful information provided by animal studies is correct, then psychotherapy for the treatment of diseases might be made more effective if some aspect of this knowledge is included in the design of the treatment. We emphasize conditioning as a regimen and an acceptable way to train the brain to remember an output pathway to raise immunity. We propose that a specific drug or perception (mild stress, represented by rotation, total body heating or handling) could substitute and kindle the same output pathway without the need for conditioning. If this view is correct, then instead of using conditioning, it may be possible to use an antigen to activate desired immune cells, and substitute a drug or an external environmental sensory stimulus (perception) to energize the output pathway to these cells. Alternatively, monitoring alterations of body temperature in response to a drug or perception might allow us to follow how effectively the brain is performing in altering immunity. Studies with animals suggest that there are alternative ways to use the mind to raise natural or acquired immunity in man.

Animals↗
PubMed1998

Serotonergic modulation of eye blinks in cat and monkey.

Serotonergic modulation of spontaneous and reflexive blinking was studied in four cats and one monkey. In cats, facial nucleus injections of the type-2 serotonin receptor (5-HT2) antagonist ketanserin tended to increase the latency of the first (R1) and second (R2) components of the blink reflex to supraorbital nerve stimulation. Injections of serotonin tended to increase and of ketanserin, to decrease the duration and amplitude of R2. Serotonin also produced unilateral blepharospasm and hemifacial spasm. In the monkey, the 5-HT2 agonist 2,5-dimethoxy-4-iodoamphetamine increased spontaneous blink frequency while ketanserin decreased both peak blink velocity and spontaneous blink frequency. These findings in cat and monkey indicate that serotonergic innervation of the facial nucleus has a behaviorally important role in modulation of spontaneous and reflexive blinks and suggest that dysfunction of serotonergic systems could be important to the pathophysiology of some cases of blepharospasm.

Animals↗
PubMed1998

Differential expression of glutamate decarboxylase messenger RNA in cerebellar Purkinje cells and deep cerebellar nuclei of the genetically dystonic rat.

The genetically dystonic rat exhibits a motor syndrome that closely resembles the human disease, generalized idiopathic dystonia. Although in humans dystonia is often the result of pathology in the basal ganglia, previous studies have revealed electrophysiological abnormalities and alterations in glutamate decarboxylase, the synthetic enzyme for GABA, in the cerebellum of dystonic rats. In this study, we further characterized the alterations in cerebellar GABAergic transmission in these mutants by examining the expression of the messenger RNA encoding glutamate decarboxylase (67000 mol. wt) with in situ hybridization histochemistry at the single cell level in Purkinje cells and neurons of the deep cerebellar nuclei. Glutamate decarboxylase (67000 mol. wt) messenger RNA levels were increased in the Purkinje cells and decreased in the deep cerebellar nuclei of dystonic rats compared to control littermates, suggesting opposite changes in GABAergic transmission in Purkinje cells and in their target neurons in the deep cerebellar nuclei. In contrast, levels of glutamate decarboxylase (67000 mol. wt) messenger RNA in the pallidum, and of enkephalin messenger RNA in the striatum, were unaffected in dystonic rats. The data indicate that both the Purkinje cells and GABAergic neurons of the deep cerebellar nuclei are the site of significant functional abnormality in the dystonic rat.

Animals↗
PubMed1998

Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat.

The purpose of this study was to characterize neuronal activity in the deep cerebellar nuclei of the unanesthetized genetically dystonic rat during the neonatal period when the clinical signs of the dystonic syndrome first appear. Previous lesion studies have established cerebellar output as critical to the expression of the dystonic rat's motor syndrome, a disorder that closely resembles generalized dystonia in humans. In the dystonic rat, both cerebellectomy and selective lesions of the deep cerebellar nuclei decrease the frequency of abnormal motor signs and improve performance on tests of motor function. Single-unit activity was recorded from the medial, interpositus and lateral cerebellar nuclei in awake normal (N=49) and dystonic (N=54) rats at postnatal days 12-26. One hundred and eighty-three cells were isolated, 91 from normal and 92 from dystonic rats. Interspike interval histograms, autocorrelations and ratemeter histograms were generated for each cell's spike train. Interspike interval histograms were modeled with single and double gamma distributions. Cells from dystonic rats as young as 12 days of age showed bursting firing patterns, positively skewed or bimodal interspike interval histograms, and sinusoidal autocorrelations. Bursting activity increased linearly with postnatal age in dystonic rats. Cells from normal rats demonstrated non-sinusoidal autocorrelations and unimodal interspike interval histograms. Spike frequency increased linearly with postnatal age in both normal and dystonic rats. There were no statistically significant group differences in spike frequency between normal and dystonic rats. These findings show that functional neuropathology can be detected at the level of single neurons in the deep cerebellar nuclei at the earliest behavioral stages of the dystonic rat's movement disorder. The degree of abnormality in spike train parameters correlates with the severity of the movement disorder. Independent of neuronal firing rates, abnormal neuronal firing patterns can serve as a guide to the localization of pathological cell populations within the central nervous system. These results provide additional evidence that abnormal cerebellar output plays a critical role in the pathophysiology of the dystonic rat's motor syndrome.

Aging↗
PubMed1997

Blink reflex to supraorbital nerve stimulation in the cat.

Neurophysiological studies of the blink reflex to supraorbital nerve stimulation were conducted in eight alert, adult male cats. The cat, like other mammals, shows both short-latency (R1) and long-latency (R2) orbicularis oculi electromyographic (OOemg) components. Measures of OOemg latency, duration, integrated area, and maximum amplitude (MA) were obtained at a stimulus magnitude of 1.5xR2 threshold. The mean (+/-SE) minimal latencies for R1 and R2 were 8.26+/-0.85 and 22.97+/-1.53 ms, respectively. On average, R1 MA was larger than R2 MA. R1 and R2 area measures were similar. Three stimulus paradigms were tested. In a paired-stimulus paradigm, the interstimulus interval (ISI) was randomly varied from 100 to 1200 ms. Ratios were constructed for the OOemg area and MA by dividing the test response by the conditioning response. In this paradigm, although a significant linear relationship was observed only between ISI and R2 MA, conditioning effects were noted on both R1 and R2 area and MA test responses at several ISIs. In a habituation paradigm, both R2 and R1 showed habituation at stimulus frequencies from 0.5 to 2 Hz. In a stimulus-response paradigm, stimulus magnitude was randomly varied between threshold and 2xthreshold. In this paradigm, OOemg area and MA of both R1 and R2 were linearly related to stimulus magnitude. Neither the systemically administered centrally acting alpha2-adrenergic antagonist yohimbine nor agonist clonidine had significant effects on blink reflex parameters, habituation, or the paired-stimulus paradigm. Overall, these results suggest that there are important similarities in the control and modulation of the R1 and R2 components of the blink reflex to supraorbital nerve stimulation in cats.

Adrenergic alpha-Agonists↗
PubMed1997

Psychoneuroendocrine immunology: site of recognition, learning and memory in the immune system and the brain.

How the interaction between the brain and immune system takes place has not been clearly defined. Because multiple changes are occurring simultaneously in all organ systems (e.g., cardiovascular, gastrointestinal, reproductive, renal, respiratory, immune, CNS), how many single systems interacts with the brain becomes extraordinarily difficult to understand. The problem boils down to developing an approach that not only allows one to study the whole organism and define the mediators of the interacting systems, but also permit one to establish the connection and physiologic relevance of the responses that are being evaluated. Conditioning, a phenomenon made popular by the work of Pavlov (1906, 1927), may provide insight into the pathways of communication between the brain and possibly any organ system of the body. Conditioning allows one to separate the afferent from the efferent circuits. That is, signals from the immune system to the CNS (IS-->CNS) can be effectively separated from signals from the CNS to immune system (CNS-->IS). This permits one to study each pathway individually. Simple, single association trial models to condition fever, natural killer (NK) cell and cytotoxic lymphocyte (CTL) activities have been developed to evaluate the pathways. Single trial learning is not new. Pavlov has observed that "The electric buzzer set going before administration of food established a conditioned alimentary reflex after only a single combination," whereas the reverse order of presentation failed to condition the animal (Pavlov 1927 p. 27). Thus, conditioning can be used to train the brain to activate the immune system and other organ systems participating in the response. During the course of the conditioned response, presumably the CNS via the hypothalamus integrates in a cohesive orderly fashion all input and output signals and coordinates the responses made by the brain to the organ systems. The odor of camphor, the conditioned stimulus (CS) can be associated with the response produced by an unconditioned stimulus (US). The unconditioned stimuli used are poly I:C to raise fever and nonimmunospecific NK cell activity or alloantigens to raise immunospecific CTL activity. The unconditioned stimulus serves only as a means to activate the immune system and unbalance the homeostasis so that a transient but new bidirectional communication loop can be established between the immune system and the CNS (IS<-->CNS). The expression of the conditioned response (i.e., elevation of fever, NK cell, or CTL activity) induced with the CS (odor stimulus) is an outcome of neural activity (CNS-->IS). This infers that during conditioning, the signals generated by the CS and US imprints a neural pathway located within the central nervous system and leaves behind a CS/US memory of the association. The immune activity (NK cell or CTL activity) which is modulated indicate that the memory pathway was activated in the brain of the animal expressing the conditioned response. The immune cells that are modulated can be considered to be casual bystander cells. These cells however must be in the proper (ready) state of activation to receive salient signals from the brain. Along with changes in the indicator cell population, other complex physiological processes are altered by the brain via sympathetic and neuroendocrine pathways to raise the fever response. These observations suggest that the physiological changes which are being evaluated such as fever, NK cell or CTL activities or perhaps blood pressure, heart rate, fat metabolism, oxygen consumption serve only as indicators (readouts), and infer that the CNS has made a coordinated reply in response to the CS signal.

Humans↗
PubMed1996

Adrenergic agents inhibit rapid increases in cerebellar Purkinje cell glutamic acid decarboxylase (GAD67) mRNA levels after climbing fiber lesions or reserpine treatment.

Loss of the inferior olive-climbing fiber input to the cerebellar cortex after treatment with the neurotoxin 3-acetylpyridine (3-AP) has been reported to double the simple spike activity of the cerebellar Purkinje cell and eliminates complex spike activity. This is quickly followed by a three- to fourfold increase in Purkinje cell mRNA for the 67 kDa form of glutamic acid decarboxylase (GAD), a synthetic enzyme for the neurotransmitter GABA. Treatment with the indirectly acting sympathomimetic amphetamine or the direct acting beta 2 adrenergic agonist clenbuterol inhibited the increase in GAD67 mRNA, and this inhibition was blocked by pretreatment with the beta receptor antagonist propranolol. The activity-enhancing effect of 3-AP treatment on cerebellar neurons was confirmed by extracellular recordings. Clenbuterol treatment prevented the increase in neuronal firing without altering lesion induction or the loss of complex spikes, and propranolol treatment produced a partial reversal of the inhibitory effect of clenbuterol on the neuronal firing rate. These results suggest that beta receptor-mediated effects on cerebellar neuronal activity may prevent the increase in mRNA levels, but that firing rate-independent beta-mediated effects on genomic expression may also play a role. A role for noradrenergic systems in modulating GAD67 mRNA is also supported by the finding that reducing endogenous cerebellar norepinephrine levels by treatment with reserpine increased Purkinje cell GAD67 mRNA levels (250% of control), and this also was inhibited by clenbuterol treatment.

Adrenergic Agents↗
PubMed1996

An easily constructed carbon fiber recording and microiontophoresis assembly.

Traditional multibarreled pipette electrodes are still widely used in microiontophoresis studies. Although better electrodes have been introduced, they are difficult and time-consuming to make. Construction of a carbon fiber recording and microiontophoresis assembly is described here. The construction of a carbon fiber electrode assembly is easy and carbon fibers have excellent characteristics for recording extracellular single unit activity. Signal-to-noise ratio of the carbon fiber electrode is maintained when combined with microiontophoresis. The electrode assembly can be used repeatedly, if cleaned properly, and it can be used to make marking lesions upon completion of an experiment.

Animals↗
PubMed1995

Selective elimination of cerebellar output in the genetically dystonic rat.

The genetically dystonic (dt) rat, an autosomal recessive mutant, exhibits a progressive motor syndrome that resembles the generalized idiopathic dystonia seen in humans. Even with supportive measures, dt rats die before reaching maturity. A total cerebellectomy that includes the dorsal portions of the lateral vestibular nuclei (dLV) eliminates the dystonic motor syndrome of the dt rats, greatly improves motor function, and prevents early death. The selective elimination of cerebellar nuclei was used to determine the cerebellar components critical to the mutant's motor syndrome. Bilateral electrolytic and/or excitatory amino acid lesions of the medial cerebellar nucleus, nucleus interpositus, lateral cerebellar nucleus and dLV were created in separate groups of 15-day-old dt rats. Rats were observed for the presence of abnormal motor signs (falls, twists, clasps, pivots) and tested on several measures of motor performance (activity, climbing, righting, homing, hanging) before surgery and again on Postnatal Day 20. All nuclear lesions produced significant improvements in motor function and decreases in the frequency of abnormal motor signs. Electrolytic lesions of the dLV were associated with the greatest improvements.

Animals↗
PubMed1994

Role of arcuate nucleus of the hypothalamus in the acquisition of association memory between the CS and US.

A single trial association protocol was used to demonstrate a conditioned increase in natural killer (NK) cell activity. The signals used were odor of camphor as the conditioned stimulus (CS) and polyinosinic-polycytidylic acid (poly I:C) as the unconditioned stimulus (US). This model has been used to dissect the underlying mechanisms of interaction between the central nervous system (CNS) and the immune system (IS) and vice versa. Here, we demonstrate the potential role played by the arcuate nucleus of the hypothalamus in the acquisition of association memory between the CS and the US. Chemical destruction of the arcuate nucleus with monosodium glutamate (MSG) was used for this purpose. Mice with arcuate nucleus lesion prior to the association protocol did not demonstrate a conditioned increase in NK cell activity. However, the lesion has no effect if produced prior to exposure to the CS at recall. These studies demonstrate the significant role played by the hypothalamus (arcuate nucleus) in a conditioned response.

Adrenocorticotropic Hormone↗
PubMed1994

Inferior olive serotonin and norepinephrine levels during development in the genetically dystonic rat.

The dystonic (dt) rat is an autosomal recessive mutant with a motor syndrome that shares several features with idiopathic torsion dystonia in humans. In the dt rats, marked biochemical and physiological abnormalities have been localized to the olivo-cerebellar system. At the pharmacological level, the dt rats exhibit enhanced sensitivity to the behavioral effects of serotonergic (5HT) agonists, including quipazine, a drug that activates the neurons of the inferior olive (IO). High performance liquid chromatography with electrochemical detection was used to assay 5-HT, 5-hydroxyindoleacetic acid (5HIAA), and norepinephrine (NE) in micropunches of the IO in normal and dt rats at 14, 18 and 22 days of age. Samples of the rostral frontal lobes were used as internal controls. Significant age-dependent effects were seen on 5-HT and 5-HIAA levels in the IO, but not the frontal cortex, in both groups. Although both groups reached similar 5-HT levels by postnatal day 22, a significant interaction effect between age and phenotype indicated a difference in the pattern of development. Administration of quipazine (10 mg/kg, IP) to 18-day-old normal and dt rats 1 h prior to sacrifice caused significant reductions in NE, 5-HIAA and the ratio of 5-HIAA to 5-HT; however, no phenotypic differences were detected. The findings do not suggest that the differential behavioral responses to 5-HT agonists seen in normal and dt rats are the result of global abnormalities in 5-HT systems, nor do they suggest the presence of presynaptic defects in the IO.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1993

An absence of changes in sigma receptor subtypes in the brains of genetically dystonic (dt) rats.

Binding sites for the sigma ligand [3H]di-o-tollylguanidine ([3H]DTG) have been reported to be altered in the brains of genetically dystonic rats. In the present study, selective sigma 1 and sigma 2 assay conditions were utilized in an effort to define which subpopulation of [3H]DTG binding sites is altered in the dystonic strain (dt). Both this approach and a re-examination using conditions similar to the previous report failed to confirm a difference between the brains of dystonic and normal rats in terms of sigma binding. Although not directly negating the possible involvement of sigma receptors in dystonia, these results indicate that sigma 1 and sigma 2 receptors appear unchanged in dystonic rats.

Animals↗
PubMed1993

Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat.

The genetically dystonic (dt) rat is a neurological mutant that displays a movement disorder characterized by repetitive twisting movements of the trunk and limbs. Previous work has identified the cerebellum of the dt rat as a site of biochemical, metabolic, and functional abnormality. In order to test the hypothesis that a cerebellar defect is critical to the expression of the motor syndrome, groups of dt rats and phenotypically normal littermates underwent cerebellectomy (CBX) at either 15 or 20 days of age. The performance of these animals on a battery of motor tasks was compared with their preoperative performance. Age-matched unoperated rats of the same phenotype and a group of dt rats with lesions in the entopeduncular nuclei (ENTO) served as controls. In dt rats, CBX permanently eliminated all motor signs of the disease except pivoting movements without reducing overall levels of activity. In the dt rats, CBX also caused significant improvement in several tests of motor function. The ENTO group, however, showed an increase in motor signs and no improvement in motor function. The results of this study provide the first evidence that the abnormalities detected in the cerebellum of the dt rat are causally related to the motor syndrome and suggest that abnormal cerebellar output may contribute to the expression of motor signs in some human dystonias.

Animals↗
PubMed1992

Abnormal cerebellar output in rats with an inherited movement disorder.

Biochemical and metabolic mapping techniques have consistently identified the deep cerebellar nuclei (DCN) of the genetically dystonic rat as a site of abnormality. Extracellular single-unit recording techniques were used to assess the functional significance of these findings in affected rats and normal littermates between 16 and 25 days of age. Cells in the medial nucleus of the mutant rats had significantly increased spontaneous firing rates in comparison with cells from normal rats. In both the medial and the interpositus nuclei, cells from the mutants fired more rhythmically than those from the normal rats. When harmaline was administered systemically to activate the olivo-cerebellar system, in normal rats, increased firing rate and bursting patterns of activity were seen. There was no reliable change in the average firing rate or rhythmicity of cells in the medial nucleus of the dystonic rats, although previous studies have shown that harmaline activates neurons in the inferior olive in the mutants. It is likely that naturally stimulated olivary activity also fails to modulate cerebellar output in this model of inherited movement disorder. Anatomical studies did not reveal any consistent changes in the number of Purkinje cells, the volume of the DCN, or the soma size of DCN neurons. Since the electrophysiological findings cannot be ascribed to a loss of the Purkinje cells that normally provide an inhibitory input to the cerebellar nuclei, the results of this study indicate the presence of a functional defect in the control of cerebellar output in the dystonic rat that accounts for the failure of these animals to display harmaline tremor and which may be critical to the motor syndrome.

Animals↗
PubMed1992

Acquisition of enhanced natural killer cell activity under anesthesia.

An increase in natural killer (NK) cell activity can be conditioned with a one trial learning paradigm to demonstrate the interaction between the central nervous system (CNS) and the immune system. In order to demonstrate learning possibilities during 'non-conscious' state, mice were anesthetized with a ketamin/rompun mixture and underwent one trial learning with odor cue as the conditioned stimulus (CS) preceding the unconditioned stimulus (US). The results indicated that mice that were exposed to camphor odor cue under the influence of anesthesia can associate the signal with the poly I:C unconditioned stimulus and were able to recall the conditioned response upon reexposure to the CS. Secondly, the conditioned association made in a conscious state can be recalled by exposure to the same olfactory odor cue in a 'non-conscious' state. The increase in the conditioned change in NK cell activity of both situations was significantly higher than the control group. The results demonstrate that learning can take place and the learned response can be recalled under the reduced awareness caused by anesthesia. The findings we report are unusual and novel in that they demonstrate that the CNS can learn new associations under conditions where the host is apparently unaware of the signals being linked. Anesthesia combined with the long interstimulus interval indicates that certain neuronal pathways in the CNS are receptive to second signals (elicited by the US) even when the second signal is separated by one day. This means the conditioned learning of a physiological response can take place unconsciously at a separate level and under situations where the host is totally unaware of the events which the brain is processing and linking as incoming information.

Anesthesia↗
PubMed1991

Effect of harmaline on cells of the inferior olive in the absence of tremor: differential response of genetically dystonic and harmaline-tolerant rats.

The genetically dystonic rat is insensitive to the tremorogenic effects of harmaline. This behavioral deficit has been linked to a defect in the olivocerebellar pathway, since few Purkinje cells of dystonic rats show a normal increase in rhythmic complex spike activity following harmaline. In normal rats, the Purkinje cell response to harmaline and tremor are initiated by a rhythmic increase in neuronal firing in the caudal inferior olive. The present single unit recording study was conducted, therefore, to determine if the inferior olive of the dystonic rat is activated by harmaline. Olivary unit responses to harmaline were also examined in normal rats made tolerant to harmaline tremor. These rats are behaviorally insensitive to harmaline and also fail to display rhythmic complex spike activity but do not have the motor deficits of the mutant rats. The spontaneous firing rate of neurons in the caudal and rostral inferior olive of the dystonic rat was significantly slower than that of phenotypically normal littermates. Despite this, all cells recorded in the caudal portion of the medial accessory olive of both dystonic and normal rats showed increased rhythmic activity following harmaline injection. Thus, the failure of the mutants to show harmaline tremor is not due to a failure of the drug to activate cells in the olive. Rather, the data suggest a defect in the subsequent transmission of this information. Unlike the control and dystonic rats, harmaline-tolerant rats failed to show sustained rhythmic activity in the inferior olive. These findings suggest that chronic treatment with harmaline may interfere with harmaline tremor at the level of the inferior olive.

Animals↗