A systematic review and meta-regression of the prevalence and incidence of perinatal depression.

BACKGROUND: Major Depressive Disorder (MDD) is a leading cause of the disease burden for women of childbearing age, but the burden of MDD attributable to perinatal depression is not yet known. There has been little effort to date to systematically review available literature and produce global estimates of prevalence and incidence of perinatal depression. Enhanced understanding will help to guide resource allocation for screening and treatment. METHODS: A systematic literature review using the databases PsycINFO and PubMed returned 140 usable prevalence estimates from 96 studies. A random-effects meta-regression was performed to determine sources of heterogeneity in prevalence estimates between studies and to guide a subsequent random-effects meta-analysis. RESULTS: The meta-regression explained 31.1% of the variance in prevalence reported between studies. Adjusting for the effects of all other variables in the model, prevalence derived using symptom scales was significantly higher than prevalence derived using diagnostic instruments (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.3-2.0). Additionally, prevalence was significantly higher in women from low and middle income countries compared to women from high income countries (OR 1.8, 95% CI 1.4-2.2). The overall pooled prevalence was 11.9% of women during the perinatal period (95% CI 11.4-12.5). There were insufficient data to calculate pooled incidence. LIMITATIONS: Studies in low income countries were especially scarce in this review, demonstrating a need for more epidemiological research in those regions. CONCLUSIONS: Perinatal depression appears to impose a higher burden on women in low- and middle-income countries. This review contributes significantly to the epidemiological literature on the disorder.

Founding events influence genetic population structure of sockeye salmon (Oncorhynchus nerka) in Lake Clark, Alaska.

Bottlenecks can have lasting effects on genetic population structure that obscure patterns of contemporary gene flow and drift. Sockeye salmon are vulnerable to bottleneck effects because they are a highly structured species with excellent colonizing abilities and often occupy geologically young habitats. We describe genetic divergence among and genetic variation within spawning populations of sockeye salmon throughout the Lake Clark area of Alaska. Fin tissue was collected from sockeye salmon representing 15 spawning populations of Lake Clark, Six-mile Lake, and Lake Iliamna. Allele frequencies differed significantly at 11 microsatellite loci in 96 of 105 pairwise population comparisons. Pairwise estimates of FST ranged from zero to 0.089. Six-mile Lake and Lake Clark populations have historically been grouped together for management purposes and are geographically proximate. However, Six-mile Lake populations are genetically similar to Lake Iliamna populations and are divergent from Lake Clark populations. The reduced allelic diversity and strong divergence of Lake Clark populations relative to Six-mile Lake and Lake Iliamna populations suggest a bottleneck associated with the colonization of Lake Clark by sockeye salmon. Geographic distance and spawning habitat differences apparently do not contribute to isolation and divergence among populations. However, temporal isolation based on spawning time and founder effects associated with ongoing glacial retreat and colonization of new spawning habitats contribute to the genetic population structure of Lake Clark sockeye salmon. Nonequilibrium conditions and the strong influence of genetic drift caution against using estimates of divergence to estimate gene flow among populations of Lake Clark sockeye salmon.

Electrical properties affecting discharge of units of the mid and posterolateral thalamus of conscious cats.

Discharge properties in response to intracellularly applied, rectangular currents were measured in units of the mid (lateralis dorsalis and centrolateral nuclei) and posterolateral (lateralis posterior and pulvinar nuclei) thalamus of conscious cats. A separate aim was to determine if neuronal excitability changed in association with changes in stimulus-evoked activity after the animals were trained to discriminate between two acoustic stimuli when performing a conditioned motor response. Low threshold spike (l.t.s.) discharges were observed in three of 272 cells given 1 nA intracellular, hyperpolarizing current pulses of 40 ms duration. This finding supports the view that thalamic neurons of conscious animals operate mainly in the relay as opposed to the oscillatory mode. Application of larger and longer hyperpolarizing currents in the cells produced rebound l.t.s. discharges, supporting the expectation that most thalamic neurons are capable of producing this type of discharge. Decrements of spike afterhyperpolarizations (AHP) and broadening of spike bases upon repeated discharge also were observed in each area of the thalamus studied. After conditioning, changes were found in the posterolateral thalamus (but not in the mid-thalamus) in the proportions of cells with spontaneous, rapid (>/=50 Hz), repetitive, discharges (RRD) and rapid, sustained discharges at rates >/=100 Hz during application of depolarizing current (RSD). In the posterolateral thalamus the percentage of units responding to 1 nA depolarization with RSD fell from 71% before conditioning to 45% after conditioning. The percentage of cells with RRD decreased from 69% to 46%. The changes were accompanied by a 3 mV hyperpolarization of the membrane potentials of the cells and a decrease in baseline activity. After conditioning, increases in excitability were found in cells of the mid thalamus that responded selectively to the click conditioned stimulus (CS) that elicited the conditioned response, and decreases in excitability were found in cells of the posterolateral thalamus that responded to the discriminative acoustic stimulus (DS) to which the animals were trained not to respond. An earlier study showed a potentiation of discharge in response to the CS in units of the midthalamus after similar conditioning and a reduction of the proportion of DS responsive units and peak discharge to the DS in units of the posterolateral thalamus. We conclude that the discharge properties of units of the mid and posterolateral thalamus can change to support discrimination between acoustic stimuli of different functional significance after conditioning.

Glutamate induces different neuronal conditioned responses than ACPD when used as a locally ionophoresed unconditioned stimulus in the cat motor cortex.

Single unit recordings were made from the motor cortex of conscious cats with glass micropipettes that allowed ionophoretic application of 0.5 M glutamate in 2 M NaCl or 0.5 M ACPD (1S,3R-1-amino-cyclopentane-1,3-dicarboxylic acid, a mGluR agonist) in 2 M NaCl. Activity in response to a 70 dB click (1 ms rectangular pulse to loudspeaker) was studied before, during, and immediately after applying each agent locally as a paired US (90 nA current 570 ms after click for 300 ms in combination with glabella tap). A 70 dB hiss sound was presented 4.4 sec after the click as a discriminative stimulus (DS). CS and DS were presented 10 times initially (adaptation); then CS, US plus tap, and DS (approximately 10 times as conditioning); and then CS and DS (2-10 times to test post-conditioning). Glutamate potentiated the mean, early, 8-16 ms response to the click after conditioning (t=18.2, p<0.0001), but not the baseline activity which decreased from a mean of 17 spk/sec to 7 spk/sec (t=3.71, p<0.001). Baseline activity increased to 31 spk/sec when glutamate was applied during conditioning (t=3.30, p<0.005). ACPD reduced the intermediate, 64-72 ms response to the click after conditioning (t=8.18, p<0.0001), and potentiated the late 104-112 ms response (t=15.4, p<0.0001). Baseline activity was slightly increased after conditioning with ACPD. Saline did not potentiate the response to click. The results indicate that glutamate agonists that differ in their receptor affinities can induce different CRs when used as locally applied USs to condition neuronal responses to a click CS in the motor cortex of cats.

T-cell clones derived by CD3 stimulation from hepatitis C virus explanted liver tissue are not representative of dominant clones present in vivo.

Liver tissue from hepatitis C virus (HCV)-related end-stage disease contains T-cell infiltrates. The goal of this study is to determine whether CD4 T-cell clones established in vitro using an antigen-independent technique from explanted liver tissue (n = 3) are representative of dominant clones present in vivo. T-cell receptor (TCR) use by intrahepatic CD4 T cells was assessed by spectratype analysis. Clones were established from single CD4 T cells by culturing in vitro with anti-CD3 and interleukin-2 (n > 25 per patient). TCR genes expressed by each clone were identified by sequencing. When identical clones were isolated, the original spectratype was analyzed further to determine whether the clone was a dominant T-cell expansion in vivo. Evidence for clonal expansions was found in all patients by spectratyping. T cells expressing the same TCRBV genes used for spectratyping were cloned in vitro. Duplicate clones expressing the same TCR genes were observed in 2 patients. Confirmation that clones established in vitro matched those present in vivo was obtained for 2 clones. Many dominant clones identified by spectratyping did not proliferate in vitro. Although spectratyping suggested the widespread accumulation of clonal expansions in HCV-related end-stage liver disease, clones established in vitro using anti-CD3 were poorly representative of dominant clones present in vivo. Although cloning with anti-CD3 has the advantage of generating T-cell clones not biased a priori toward a specific antigen, modified cloning strategies will need to be developed to expand those clones that appear dominant in end-stage organs.

Changes in potentiation and timing of sensorimotor transmission after adaptation of a postsynaptic transient outward current in a simulated cortical neuron.

How adaptation of a postsynaptic transient outward current might affect the efficacy of sensorimotor transmission was investigated. The transmission signals that were studied were a 5 ms conditioned stimulus (CS) and a 60 ms US drawn from intracellularly recorded, depolarizing postsynaptic potentials (PSPs) elicited in pyramidal neurons of the cat motor cortex by a click CS and a glabella tap US, respectively. SPICE, a program used to analyze electrical circuits, was used to simulate the cortical neuron containing the adaptive outward current. Changes in the magnitude and latency of rise to firing threshold of the PSPs were compared i) after presynaptic augmentation of a CS input in the absence of an adaptive postsynaptic current and ii) after decreasing the magnitude of an adaptive postsynaptic current that was rapidly activated by depolarization. Effects of short (6 ms) and long (24 ms) inactivation time constants of the postsynaptic current were also studied. In both presynaptic adaptation and postsynaptic adaptation, the potentiation of the magnitude of the CS-induced PSP was similar, with the latency to threshold being reduced by < or = 1 ms in both cases. The effects on the US PSP differed. Presynaptic adaptation affecting the CS had no effect on the US. Adaptation of the CS by a postsynaptic outward current with a 6 ms inactivation time constant, reduced the latency to threshold of an EPSP from a nearby US synapse by up to 6 ms by augmenting the initial portion of the slowly rising US-induced PSP. Adaptation of a postsynaptic current with a 24 ms inactivation time constant reduced the latency of response to the US PSP by up to 16 ms. When the US synapse was relocated to the soma, the reduction in US latency caused by adaptation of the outward current at the CS synapse was reduced by up to one half. The latency of slowly rising components of integrated synaptic responses to compound CSs of > 5 ms duration from multiple synaptic inputs would be expected to show reductions corresponding to those of the US. We conclude that potentiation of synaptic transmission by adaptation of a postsynaptic outward current can result in reductions of latency of sensorimotor transmission that can significantly affect the timing and accuracy of controlled motor tasks. These effects depend significantly on the locations of the synaptic inputs within the cell.

Multiple representations of information in the primary auditory cortex of cats. II. Stability and change in early (<32 ms), rapid components of activity after conditioning with a click conditioned stimulus.

Activity was recorded from single units of the A(I) cortex of awake animals to identify early (<32 ms) components of the population response to a 70 dB click and establish if they changed after using the click as a CS for conditioning. A 70 dB hiss was used as a discriminative stimulus. Responses to these stimuli were compared before and after a forward order of pairing that produced conditioning and a backward order of pairing that produced weak sensitization (backward conditioning). Averages of discharges in 2 and 4 ms bins distinguished primary (8-12 ms) from secondary (12-16 ms) temporal components of response to the click, and confirmed that the onset of the response was shorter in A(I) (8 ms, mean of 647 units) than in the adjacent, A(II) cortex (16 ms, mean of 95 units). (All times include a 1.6 ms transmission delay in sound arrival.) Primary and secondary components of A(I) responses to click did not change uniformly after changes in behavioral state, and were affected differently by both conditioning and backward conditioning. The percentage of cells with onsets of response to the click at secondary latencies (and to the hiss at tertiary latencies) increased after backward conditioning but not after conditioning, as did the magnitude of activity in response to the click. (The latter had a lesser degree of increase after conditioning.) The primary response to the click did not show these increases. The non-uniform changes suggested that temporal processing of the click was conducted differently in the 8-12 ms post stimulus period than in the 12-16 ms period. Within the total population of cells, it was possible to identify a small subgroup (13%) of highly auditory-responsive units that showed an increased primary response to the click as a CS selectively after conditioning and not after backward conditioning. The secondary component of response in these cells increased after both conditioning and backward conditioning. The percentages of cells responding to the click and hiss at primary latencies did not change significantly after conditioning, even in the subgroup of highly responsive cells. The results characterize differently timed components of rapid responses to acoustic stimuli in the A(I) cortex, disclose significant temporal differences in primary, secondary and tertiary information processing that affect the representations of the transmitted acoustic message across different behavioral states, and find one representation in a small subgroup of cells that supports the hypothesis that cells of the A(I) cortex have a selectively potentiated response to the CS after conditioning.

Multiple representations of information in the primary auditory cortex of cats. I. Stability and change in slow components of unit activity after conditioning with a click conditioned stimulus.

Recordings of activity were made from 647 single units of the A(I) cortex of awake cats to evaluate behavioral state-dependent changes in the population response to a 70-dB click. Averages of PST histograms of unit activity were used to assess the changes in response. This report focuses on slow components of the responses disclosed by averages employing bin widths of 16 ms. Responses were compared before and after a Pavlovian blink CR was produced by forward pairing of click conditioned stimuli (CSs) with USs. A backward-paired 70-dB hiss was presented as a discriminative stimulus. Studies were also done after backward pairing of the click CSs (backward conditioning) that produced weak sensitization instead of a conditioned response. There were four main findings. First, components of activity elicited 32-160 ms after presenting the hiss decreased significantly after conditioning and after backward conditioning. The decreases after conditioning represented the most pronounced changes in activity evoked by either clicks or hisses in this behavioral state. Second, baseline firing decreased after both conditioning and backward conditioning. The direction of baseline change was opposite that found in adjacent cortical regions and in A(I) cortex after operant conditioning employing an acoustic cue. Third, prior to conditioning, unit activity in response to the hiss declined before the sound of the hiss reached its peak or terminated. This decrease was thought to represent a habituatory adaptation of response to a prolonged acoustic stimulus. This type of habituation to a lengthy stimulus has been recognized, behaviorally, but has not been observed previously in the activity of units of the auditory receptive cortex. Fourth, the percentage of click responsive units did not change significantly after the click was used as a CS for conditioning, and despite the accompanying changes in baseline activity, the absolute levels of activity summed in the first 16 ms after click delivery remained stable across behavioral states in which the motor response to the click was altered profoundly. The onset of the conditioned motor response began 20 ms after the click, and was shown earlier to depend on rapid, potentiated transmission through the cochlear nucleus and motor cortex for its generation. Thus the stability of the response to the click in the primary auditory receptive cortex was unexpected. This led us to make further analyses of the data with 2- and 4-ms bin widths (see companion report) that eventually disclosed a potentiated response to the click. The findings show stability and change in the response to the click as a CS, depending on the band pass (bin width) used for analysis of spike activity. In the representation disclosed by low pass filtering in this study, the response was stable. This representation provided information suitable for identifying commonalties of the click signals across varying behavioral states. The representations of the click and hiss contained in the slow components of the population response in the A(I) cortex were uncorrelated with the selective potentiation of activity in motor cortex and behavioral performance in response to click as a CS after conditioning. Although changes in the activity evoked by hisses occurred after conditioning, the changes also occurred after backward conditioning when only small, sensitized behavioral responses to clicks and hisses were observed. Basic theoretical considerations about information transmission in complex neural networks plus clinical observations comparing derangements of linguistic and non-linguistic cortical functions in humans suggest that multiple representations of conditioned stimulus inputs may exist in local populations of cortical neurons. Together, our studies provide evidence for two different, concurrent representations of information about a click CS encoded in the spike activity of the A(I) cortex.

Identification of differently timed motor components of conditioned blink responses.

Electromyographic recordings were made from the orbicularis oculi muscles of cats in order to identify differently timed motor components of conditioned eye blink responses (CRs). Conditioning was established rapidly by pairing electrical stimulation of the hypothalamus (HS) with a click conditioned stimulus (CS) and a glabella tap unconditioned stimulus (US). Analysis of the EMG responses disclosed five different motor components of the CR that could be distinguished and characterized according to their latencies of occurrence. Four were associated with an increase in EMG activity elicited by the CS (16-48 ms, alpha(1); 48-80 ms, alpha(2); 80 to 120 ms, beta; >/=120 ms, gamma), and one was associated with a decrease in activity (16 to 60 ms, alpha(i)). Analysis of the amplitudes of the different components of the CR during the course of conditioning and extinction disclosed that short latency, alpha(1) components of the CRs were acquired and extinguished in a manner equivalent to longer latency components of the CRs. The observations supported the hypothesis that short and long latency components of blink responses represented comparable rather than substantially different forms of Pavlovian conditioning. The alpha(2) response was present before conditioning began, and increased with other components after conditioning. The alpha(i) response component was also observed prior to conditioning, and represents a previously undetected, inhibitory consequence of presenting weak (70 dB) acoustic stimuli. It could play a role in conditioned inhibition, latent inhibition and blocking as well as suppression of the conditioned motor response during extinction.

Differences in responses to 70 dB clicks of cerebellar units with simple versus complex spike activity: (i) in medial and lateral ansiform lobes and flocculus; and (ii) before and after conditioning blink conditioned responses with clicks as conditioned stimuli.

Activity was recorded from 554 cerebellar units in eleven conscious cats to determine if responses to 70 dB clicks differed in units with simple and complex spike discharges. Effects of region of recording and behavioral state (with click used as a conditioned stimulus for conditioning) were also assessed. Cells with only simple spikes were distinguished from cells that had the following types of complex spike events: Type I-simple or initial spike followed > 1 ms by multiple spikes with baseline displacement (classical complex spikes), Type II--followed < or = 1 ms by spikes with or without baseline displacement (spikes in the absolute refractory period should arise from a separate site of initiation), and Type III-followed by spikes and displacement too close to the baseline noise to distinguish as Type I or II. Among the groups mean baseline activity was greatest in cells with Type I complex spikes, least in cells with Type III complex spikes, and greater in Type II cells than simple cells. Significant increases in activity within 32 ms of presenting clicks were found in the groups of Type II cells and simple cells. These appear to be the main auditory responsive cells of the cerebellar regions studied. Activity of Type II cells best reflected the temporal properties of the click; responses of simple cells had slower onsets (except in flocculus) and longer durations. Responses to click in Type II and simple cells differed in recordings from: (i) lateral ansiform lobe (lateral crus I and portions of crus II), (ii) medial ansiform lobe (medial crus I), and (iii) flocculus. The largest mean responses above baseline in the first 32 ms after click were found in Type II cells of the lateral ansiform lobe with onsets of 8-16 ms. Magnitudes of response differed before and after conditioning and backward conditioning. In the lateral ansiform lobe, the < 32 ms response to click was greater in Type II than simple cells in each state, but showed a greater increase above baseline after backward conditioning when conditioned responses were not produced than after conditioning. The onset of increased activity to click conditioned stimuli in Type II cells of the lateral ansiform region preceded the onset of the blink conditioned response after conditioning, consisted almost entirely of simple spikes, and reflected an increase in magnitude of response as opposed to an increased number of responsive units. After conditioning, an increased number of units in the flocculus responded to click conditioned stimuli in the 16-24 ms post stimulus period. Of the 16 cells with an onset of increased activity at this time, eight showed only simple spike activity. Seven of the remaining eight cells (all Type II) showed a significant increase in conditioned stimulus-evoked complex spiking above the low (usually < 1/s) baseline level of complex spike discharges. The findings support the conclusions that cerebellar units can respond rapidly enough to acoustic stimuli to play a role in auditory as well as motor processing and that the responses to 70 dB clicks differ among cells with simple and complex spike discharges. The differences are influenced substantially by the region of cerebellar recording and the behavioral state. The findings in cells of the flocculus offer the first evidence that complex as well as simple spike activity can contribute to an increased probability of discharge to click as a conditioned stimulus after conditioning.

Facilitation of acoustic responses of cartwheel neurons of the cat dorsal cochlear nucleus.

Responses to clicks were increased in cartwheel cells of the dorsal cochlear nucleus of cats after pairing presentations of the clicks with local iontophoretic delivery of glutamate. The cells were identified by bursting discharges, and were recorded intracellularly in vivo. The findings indicate that inhibitory interneurons such as cartwheel cells can participate in complex adaptive acoustic signal processing. Each cell displayed doublet discharges of > 800 Hz. In 70% of the cells, some of the doublet discharges reached rates > 1000 Hz.

Induction of T cell anergy by high concentrations of immunodominant native peptide is accompanied by IL-10 production and a block in JNK activity.

The ability to induce anergy in antigen-specific T cells has potential therapeutic value for altering pathologic immune responses. This study was undertaken to further analyze changes in cytokine production and intracellular signaling during anergy induction using high concentrations of native peptide ligand of tetanus toxoid (TT)- and myelin basic protein (MBP)-specific human T cell lines. The TT-selected T cell line could be rendered unresponsive to its dominant epitope in a dose-dependent manner (IC50 = 0.03 microg/ml). The TT-selected line, as well as three T cell clones established from this line, continued to produce IFN-gamma and significantly increased IL-4 and IL-10 production when anergy was induced with high concentrations of the immunodominant epitope. JNK enzymatic activity was blocked in anergized T cells. The MBP-selected line could likewise be rendered unresponsive by incubation with supraoptimal concentrations of immunodominant peptide and anergy induction was accompanied by IL-10 release. Both T cell lines could be anergized by the autopresentation of native peptide since anergy was induced in cultures lacking fresh antigen-presenting cells. This study shows that the mitogen-activated protein kinase cascade is blocked when anergy is induced to high concentrations of soluble peptide.

1,25-Dihydroxyvitamin D3 inhibition of col1a1 promoter expression in calvariae from neonatal transgenic mice.

We studied the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on organ cultures of transgenic mouse calvariae containing segments of the Col1a1 promoter extending to -3518, -2297, -1997, -1794, -1763, and -1719 bp upstream of the transcription start site fused to the chloramphenicol acetyltransferase (CAT) reporter gene. 1,25(OH)2D3 had a dose-dependent inhibitory effect on the expression of the -3518 bp promoter construct (ColCAT3.6), with maximal inhibition of about 50% at 10 nM. This level of inhibition was consistent with the previously observed effect on the endogenous Col1a1 gene in bone cell models. All of the shorter constructs were also inhibited by 10 nM 1,25(OH)2D3, suggesting that the sequences required for 1, 25(OH)2D3 inhibition are downstream of -1719 bp. The inhibitory effect of 1,25(OH)2D3 on transgene mRNA was maintained in the presence of the protein synthesis inhibitor cycloheximide, suggesting that the inhibitory effect on Col1a1 gene transcription does not require de novo protein synthesis. We also examined the in vivo effect of 1,25(OH)2D3 treatment of transgenic mice on ColCAT activity, and found that 48 h treatment caused a dose-dependent inhibition of CAT activity in calvariae comparable to that observed in organ cultures. In conclusion, we demonstrated that 1,25(OH)2D3 inhibits Col1A1 promoter activity in transgenic mouse calvariae, both in vivo and in vitro. The results indicate that there is a 1, 25(OH)2D3 responsive element downstream of -1719 bp. The inhibitory effect does not require new protein synthesis.

Interleukin-1 represses COLIA1 promoter activity in calvarial bones of transgenic ColCAT mice in vitro and in vivo.

Interleukin-1 (IL-1) inhibits collagen synthesis in osteoblastic cell lines and primary osteoblast-like cells. However, promoter elements regulating type I collagen A1 (COLIA1) expression in vivo and in organ culture may differ from those regulating expression in cell culture. We have examined the effects of IL-1 on reporter gene activity in neonatal transgenic mouse calvariae bearing COLIA1 promoter-chloramphenicol acetyltransferase (ColCAT) fusion genes. The parent construct, ColCAT 3.6, contains 3.5 kb of 5' flanking sequence and 115 bp of 5' untranslated region fused to the CAT reporter. In 48-h calvarial organ cultures, IL-1 repressed ColCAT 3.6 promoter activity and collagen synthesis in a dose-related manner, with a maximal inhibition of 40-65%. This repression was retained in 5' deletion constructs truncated to-1719 bp. The inhibition of transgene mRNA was blocked by cycloheximide, indicating a requirement for new protein synthesis. Pretreatment with indomethacin diminished the inhibitory effect of IL-1 on CAT activity and collagen synthesis, suggesting partial mediation by prostaglandins. Local in vivo injection of IL-1 (500 ng) decreased calvarial transgene mRNA after 8 h, an effect that was partially blocked by indomethacin. ColCAT transgenic mice represent a useful model for in vitro and in vivo assessment of COLIA promoter regulation by cytokines and other factors.

Acoustic transmission in the dentate nucleus. I. Patterns of activity to click and hiss; II. Changes in activity and excitability after conditioning.

Recordings were made from 95 units of the dentate nucleus of naive cats to determine if patterns of response to 70 dB clicks could be distinguished from those to another acoustic stimulus (a hiss) of approximately equal sound pressure level. Further studies of an additional 309 units were conducted to determine if unit excitability and the response to clicks changed after Pavlovian conditioning in which blink responses were elicited by the clicks as conditioned stimuli. Over 50% of units tested before conditioning responded to click or hiss with increased activity, and 8% responded in the first 4-8 ms after the onset of the rapidly rising click. Cross-correlation of the respective 160 ms poststimulus histogram averages of mean activity showed dissimilar patterns of response to clicks and hisses (Pearson product-moment correlation coefficient + 0.02). Thus the averaged population responses distinguished these stimuli. In addition, individual cells were found in each behavioral state that responded selectively to either click or hiss. After conditioning with click as the conditioned stimulus, the number of units responding in the first 4-8 ms to click increased to 23%. The mean magnitude of activity 4-8 ms after presenting the click increased after conditioning but not after sensitization produced by backward pairing of the stimuli used for conditioning. After backward pairing only 6% of the units responded in the first 4-8 ms to click. The changes in activity after conditioning were accompanied by increases in neural excitability to intracellularly applied depolarizing current. In contrast with the changes in activity, the increases in neural excitability were also found after backward pairing. We conclude that short as well as long latency acoustic transmissions to click change in the dentate nucleus after conditioning, that changes in response to click are expressed in 4-8 ms responsive cells, and that many of these cells have different patterns of spike activity in response to click and hiss. The findings support the hypothesis that the dentate nucleus can play a significant role in short as well as long latency, adaptive acoustic transmission that can enhance the response to an acoustic signal used as a Pavlovian conditioned stimulus.

The effects of chronic exercise on metabolic and reproductive functions in male rats.

Previous studies concerning the effects of swimming on various endocrine gland functions have been performed. Our study was thus designed to analyze the effects of chronic exercise (swimming) on the resting metabolic rates (RMR) of adult rats. Most of the protocols used a water temperature of 33 C. It is our contention that such a protocol is not exclusively an exercise stress, but also a hypothermic stress. The protocol of our study was designed in a way that hypothermic stress was not part of the exercise stress. Male rats were swam in 36 C water for 3 hours a day, 5 days a week for 4 months. RMR of the animals were determined 24 h after the next to last swim session. Plasma hormone levels and epididymal sperm concentrations were determined in animals sacrificed 24 h after the last swim period. Exercising animals had a RMR 16% greater than that of control animals (p < 0.02), yet total and free thyroxine and total and free triiodothyronine were not significantly elevated. Neither plasma testosterone nor epididymal sperm counts were significantly reduced in the exercising animals. It appears that chronic exercise produces an elevation in RMR which is unrelated to thyroid gland activity and does not suppress the hypothalamic-pituitary-gonadal axis.

TCRB clonotypes are present in CD4+ T cell populations prepared directly from rheumatoid synovium.

The identification of clonal T cells at sites of inflammation is hampered by the large number of polyclonal T cells that nonspecifically accumulate. In this report, we combine the use of T cell sorting with spectratyping of the third complementarity determining region (CDR3) and direct sequence analysis to rapidly screen for and identify clonal expansions of T cells from synovial tissue specimens from patients with rheumatoid arthritis (RA). Initially, we used a polymerase chain reaction specific for the variable region gene of the T cell receptor beta chain (TCRBV) to compare the TCRBV repertoire expressed by CD4+ T cells from the peripheral blood and synovium of five patients with long-standing RA. Each patient had several TCRBV genes that were amplified to a greater degree from synovium. Extensive sequence analysis (n > 170) showed that each patient contained junctional sequences that occurred more than once, implying the presence of T cell clones within the starting CD4+ T cell population. To assess a more straightforward approach to identifying clones, six additional patients were recruited and CD4+, TCRBV2+ synovial T cells were positively selected and analyzed by CDR3 spectratyping. Bands deviating from a normal distribution were excised from the gel and sequenced directly. Clones were detected in half of the patients. These data are consistent with the possibility of an antigen-driven T cell response in RA that remains present in the setting of advanced disease.

Activation of cells of cochlear nucleus by electrical stimulation of lateral hypothalamus.

Effects of electrical stimulation of the lateral hypothalamus (HS) were examined in 67 cells of the dorsal or ventral cochlear nucleus. Both short latency activity in the 10-20 ms post-stimulus period and late activity in the > 20 ms post-stimulus period were elicited in response to HS. A greater percentage of units exhibited the short latency response in dorsal (89%) than ventral (68%) cochlear nucleus. It was not previously recognized that stimulation of the hypothalamus could elicit increases in spike activity in this auditory relay nucleus. The hypothalamus is known to play a role in visceral-emotional functions, including feeding, fleeing, fighting and reproductive behavior. These results suggest a means by which neural activities supporting these functions could influence acoustic relay transmissions.