Functional lateralization of the sensorimotor cortex in patients with schizophrenia: effects of treatment with olanzapine.

BACKGROUND: Earlier cross-sectional studies with functional magnetic resonance imaging (fMRI) in treated patients with schizophrenia have reported abnormalities of cortical motor processing, including reduced lateralization of primary sensory motor cortex. The objective of the present longitudinal study was to evaluate whether such cortical abnormalities represent state or trait phenomena of the disorder. METHODS: Seventeen acutely ill, previously untreated patients were studied after 4 weeks and after 8 weeks of olanzapine therapy. Seventeen matched healthy subjects served as control subjects. All subjects underwent two fMRI scans 4 weeks apart during a visually paced motor task using a simple periodic block design. Functional magnetic resonance imaging data were analyzed in Statistical Parametric Mapping (SPM99). Region of interest analyses were used to determine a laterality quotient (an index of lateralization) of motor cortical regions. RESULTS: The fMRI data indicated that patients had reduced activation of the primary sensory motor cortex at 4 weeks but not at 8 weeks; however, the laterality quotient in the primary sensory motor cortex was reduced in patients at both time points. CONCLUSIONS: These results suggest that some cortical abnormalities during motor processing represent state phenomena, whereas reduced functional lateralization of the primary sensory motor cortex represents an enduring trait of schizophrenia.     

Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions.

BACKGROUND: Adverse life events occurring early in development may alter the correct program of brain maturation and render the organism more vulnerable to psychiatric disorders. Identification of persistent changes associated with these events is crucial for the development of novel therapeutic strategies. METHODS: We used postnatal repeated maternal deprivation (MD) from postnatal day (PND) 2-14 to investigate changes in brain-derived neurotrophic factor (BDNF) levels. RNase protection assay and enzyme linked immunosorbent assay were employed to determine the anatomic profile of neurotrophin expression at different ages following MD. RESULTS: We found that MD produces a short-term up-regulation of neurotrophin expression in hippocampus and prefrontal cortex, as measured on PND 17, whereas at adulthood, a selective reduction of BDNF expression was observed in prefrontal cortex. When adult animals were challenged with a chronic swim stress paradigm, both a reduced expression of BDNF in prefrontal cortex and a significant reduction in striatal protein levels were found only in control subjects, whereas levels in the MD group were not further decreased. CONCLUSIONS: Our data suggest that MD produces a significant reduction of BDNF expression within prefrontal cortex and striatum, which may render these structures less plastic and more vulnerable under challenging conditions.     

Blockade of Prefronto-cortical α1-Adrenergic Receptors Prevents Locomotor Hyperactivity Induced by Subcortical D-Amphetamine Injection

The stimulation of cortical dopaminergic D1 receptors can counteract the increased locomotor activity evoked by D-amphetamine application in the nucleus accumbens (Vezina et al., Eur. J. Neurosci., 3 , 1001–1007, 1991). Moreover, an α1 antagonist, prazosin, prevents the locomotor hyperactivity induced by electrolytic lesions of the ventral tegmental area (Trovero et al., Neuroscience, 47 , 69–76, 1992). Attempts were thus made to see whether blockade of α1-adrenergic receptors in the rat prefrontal cortex could reduce nucleus accumbens D-amphetamine-evoked locomotor activity. Rats implanted chronically and bilaterally with cannulae into the medial prefrontal cortex and the nucleus accumbens were used for this purpose and locomotor activity was monitored in circular corridors. Preliminary experiments indicated that intraperitoneal injection of prazosin (0.06 mg/kg) reduces the locomotor hyperactivity induced by the peripheral administration of D-amphetamine (0.75 mg/kg). This effect of prazosin was not observed when locomotor hyperactivity was obtained by an intraperitoneal injection of scopolamine (0.8 mg/kg). Bilateral nucleus accumbens injections of D-amphetamine (4.0 nmol/side) markedly increased locomotor activity, as estimated in a 30 min period. Prior (20 min) bilateral injections of either prazosin or WB-4101 (0.16 pmol) into the medial prefrontal cortex abolished the nucleus accumbens D-amphetamine-evoked response. The recovery of the nucleus accumbens D-amphetamine-evoked response was closely dependent on the amount of prazosin used, very prolonged inhibitory effects of the drug being seen with a high amount (>4 days with 160 pmol). In contrast, whatever the amount of WB-4101 used (0.16–160 pmol), recovery occurred within 3 days. It is suggested that the blockade of cortical d-adrenergic receptors facilitates locally dopaminergic D1 transmission. This latter effect may counteract the increased locomotor activity induced by the application of D-amphetamine into the nucleus accumbens.     

Increase in meso‐prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids

The intravenous administration of the psychoactive constituent of marijuana, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) (62.5–1000 μg/kg), and the synthetic cannabinoid agonist WIN 55212,2 (WIN) (62.5–500 μg/kg), produced a dose-related increase in the firing rate and burst firing in the majority of antidromically identified meso-prefrontal dopaminergic neurons. In a restricted number of neurons (n = 4), WIN administration did not increase firing rate but produced an increment of bursting activity. These effects of the cannabinoids were reversed by the intravenous administration of SR 141716 A, a selective cannabinoid antagonist (1 mg/kg), per se ineffective to modify the electrical activity of dopaminergic neurons. The results indicate that stimulation of cannabinoid CB1 receptors produces an activation of meso-prefrontal dopaminergic transmission. Considering that supranormal stimulation of D1 dopamine receptors in the prefrontal cortex has been shown to impair working memory, the present results suggest that the negative effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.     

Electrically evoked turning: asymmetric and symmetric collision between anteromedial cortex and striatum

Electrical stimulation of the anteromedial cortex (AMC) or striatum of rats evoked contraversive eye, head and body movements. In these experiments we test which neurons and which pathways are responsible for the turning by delivering conditioning (C) pulses to one site and test (T) pulses to the second site, and measuring the frequency of pulse pairs required to evoke a full turn in 10 s. Decreases in the required frequency were usually found at C-T intervals from 0.6 to 1.0 ms, whether the C pulses were delivered to the AMC or to the striatum. This symmetric effect is attributed to collision in fast-conducting axons connecting cortex and striatum. Symmetric collision at C-T intervals of 2–4 ms was observed between cortex and 3 dorsal striatal sites, suggesting slower axons from cortex to these dorsal striatal sites. In several animals, asymmetric changes in required frequency also occurred. When the C pulses were presented via the striatal electrode, the recovery in required frequency occurred at C-T intervals of 1–4 ms, but when the C pulses were presented via the cortical electrode, recovery occurred at C-T intervals of 2–50 ms. This asymmetry is attributed to indirect (i.e., transynaptic) activation of corticostriatal or striatal output axons. These results suggest that in both cortex and striatum there are synapses, transmitting from rostral to caudal, which are important for electrically evoked turning. When C and T pulses were delivered to the same site, decreases in required frequency occurred at C-T intervals from 0.4 to 4 ms, attributable to recovery from refractoriness. In 3 striatal sites, however, large changes were also seen at C-T intervals from 6 to 50 ms. In all 3 sites, asymmetric collision occurred at these same intervals. The recovery at long C-T intervals could be due to transynaptic collision also, resulting from the simultaneous activation of presynaptic and postsynaptic axons by a single striatal electrode.     

Vibrissectomy induced changes in GAP-43 immunoreactivity in the adult rat barrel cortex.

Within the rat primary somatosensory cortex, neurons responding principally to movement of each individual mystacial vibrissa are grouped together in structures termed barrels. Previous studies have examined changes in the area of cortex showing increased 2-deoxyglucose uptake in response to vibrissal stimulation. These studies have shown that chronic removal of all but the central (C3) vibrissa in adult rats induces an enlarged representation of the remaining C3 barrel in the contralateral cortex. This increase is prevented by cortical norepinephrine depletion. The major question raised by such studies is whether such plasticity is due to structural rearrangement or unmasking of otherwise silent synapses. In this study, antibodies to GAP-43, a presynaptic protein whose synthesis is related to neuronal development and regeneration, were used to investigate this issue. In adult rat brain, tangential sections through layer IV of the barrel receptor field normally show moderate levels of GAP-43 immunoreactivity (GAP-IR) in the inter-barrel septa and low levels within the barrels themselves. The present study examined changes in the pattern of GAP-IR from 1 to 8 weeks after vibrissectomy with sparing of C3 as an index of possible physical reorganization of cortical circuits. Quantitative analysis of the cortices of animals with unilateral vibrissectomy with sparing of C3 showed that the area of low GAP-IR within the barrels surrounding C3 was decreased at 1 week (8.4% shrinkage; P less than 0.01) and 8 weeks (12.0% shrinkage; P less than 0.015), relative to the cortex ipsilateral to the surgery. Both bilateral vibrissectomy with sparing of C3 and ibotenic acid lesions of the ventrobasal thalamus produced similar results. Some evidence was also seen that the area of low GAP-IR in the C3 barrel shrank to a similar degree after such manipulations. Cortical norepinephrine depletion had no apparent effect on vibrissectomy-induced GAP-IR changes. These results suggest that removal of vibrissal input to the adult rat barrel cortex produces transynaptic induction of axonal sprouting within the barrel cortex.     

Septo-hippocampal and nBM-cortical cholinergic neurones exhibit differential time-courses of activation as a function of both type and duration of spatial memory testing in mice

We previously showed that the initial acquisition session of a spatial discrimination (mixed reference/working memory) test in an 8-arm radial maze induced differential activations in the ascending cholinergic septo-hippocampal and nBM-cortical pathways in mice. This data showed that the duration of post-test cholinergic activation was longer in the nBM-cortical pathway than in the septo-hippocampal projection. Moreover, the post-test durations but not the immediate post-test amplitudes of activation in each pathway decreased progressively as a function of repeated daily acquisition sessions. In the present study we have thus tested the hypotheses that the time-courses of post-test cholinergic activation in the septo-hippocampal and nBM-cortical pathways may vary both as a function of the type of memory used (working vs. reference) and according to the duration of repeated daily testing. Cholinergic activity in vivo in the hippocampus or frontal cortex of mice was quantified using measures of sodium-dependent high-affinity choline uptake at two different times (30 s and 15 min) following specific spatial working or reference memory testing in an 8-arm radial maze. The memory tests were administered daily over a 13-day period to attain high levels of performance in each type of task. In comparison to control groups both types of memory testing induced significant post-test cholinergic activations in each brain region on Day 15. However, cholinergic activity remained elevated in frontal cortex at 15 min post-test following reference memory testing, whereas significantly shorter durations of cortical and hippocampal cholinergic activation were observed following working memory testing using short (1 min) retention intervals. The possible significance of these differential modifications to the time-course of the post-test activations in these cholinergic pathways in working and reference memory processes and the putative transsynaptic mechanisms involved are discussed.     

Recovery of olfactory behavior. I. Recovery after a complete olfactory bulb lesion correlates with patterns of olfactory nerve penetration

The olfactory system is an excellent system in which to study issues related to potential functional recovery after a debilitating brain injury. The olfactory system is well-characterized, easily accessible and there are a vast number of studies available from a variety of perspectives. The experimental aim of this research is to examine the anatomical correlates associated with potential behavioral recovery in rats that receive complete olfactory bulb lesions as neonates or as adults. The results show that behavioral recovery occurs only when olfactory nerve penetration of the central nervous system is observed. Further, both olfactory nerve penetration and behavioral recovery are age-dependent phenomena. The olfactory nerve penetration only occurs when the olfactory bulb lesion is performed in neonates. Behavioral recovery of olfactory ability follows a linear trend and reaches near normal levels during the six week behavioral testing period. Histological analysis using an antibody for olfactory marker protein (an olfactory nerve-specific marker) reveals two potential candidates for the anatomical pathway responsible for behavioral recovery: olfactory nerve to orbital frontal cortex and olfactory nerve to olfactory peduncle. This report presents evidence that recovery of olfactory ability can occur in the absence of the olfactory bulb if the lesion is performed when the rat is still a neonate.     

Signal undershoots following visual stimulation: A comparison of gradient and spin-echo BOLD sequences

Gradient-echo (GRE) and spin-echo (SE) EPI BOLD sequences were used to quantitate the effect of visual stimulation. Both sequences showed a positive BOLD response during stimulation and a negative BOLD response in the interstimulation intervals. The relaxation rate changes during stimulation were larger for the GRE sequence than for the SE sequence, whereas in the interstimulation intervals they were not significantly different. In both cases, the ratio of the GRE/SE relaxation rate changes were consistent with BOLD effects in larger vessels despite the well-known lower sensitivity of the SE sequence to the extravascular component of the BOLD effect in larger vessels. The most probable explanation of this result is that a significant fraction of the observed changes originated from the intravascular component of the BOLD effect. The SE sequence depicted smaller areas of activation than the GRE sequence with more than 85% of the pixels being depicted as significant by the SE sequence being also significant in the GRE activation maps. However, for the reverse comparison, an overlap of only 35% was observed, with many of the strongly correlated GRE pixels showing weak correlations in the corresponding SE activation image. Our results, together with the fact that signal undershoots have not been observed by groups using MR sequences that measure absolute flow changes for similar stimulation paradigms, suggest that the undershoot may be due to alterations in the blood volume and/or hematocrit during stimulation that normalize at a slower rate than the changes in blood flow after the cessation of the stimulation, leading to a poststimulation signal undershoot.     

Early development of the SI cortical barrel field representation in neonatal rats follows a lateral-to-medial gradient: an electrophysiological study

Summary Development of the barrel field in layer IV of SI cortex of neonatal rats was studied in vivo using electrophysiological recording techniques. This study was designed to determine (a) the earliest time SI cortex is responsive to peripheral mechanical and/or electrical stimulation and (b) whether the development of the SI cortical barrel field map of the body surface follows a differential pattern of development similar to the pattern previously demonstrated using peanut agglutinin (PNA) binding (McCandlish et al. 1989). Carbon fiber microelectrodes were used to record evoked responses from within the depth of the cortex in neonatal rats between postnatal day 1 (PND-1), defined as the day of birth, and PND-14. Evoked responses were first recorded approximately 12 h after birth. These responses in the youngest animals were of low amplitude, monophasic waveshape, and long latency, with long interstimulus intervals necessary to drive the cortex. Increases in amplitude and complexity of waveshape and decreases in latency were observed over subsequent postnatal days. The earliest responses recorded on middle PND-1 were evoked by stimulation of the face and/or mystacial vibrissae. The next responses were evoked approximately 24 h after birth (late PND-1) by stimulation of the forelimb. The last responses were evoked approximately 36 h after birth (middle PND-2), by stimulation of the hindlimb. The physiological map of the representation of the body surface follows a developmental gradient similar to the gradient observed using PNA histochemistry; however, the lectin-generated morphological map lagged approximately 48 h behind the physiological map. The representation of the body surface appears to be topographically organized as early as PND-2. Our results suggest that thalamocortical afferents have reached the developing cortical plate and are functional before glial cells are first detected. These results do not sit well with a theory of barrel field development based entirely on the role of glia in pattern formation.