Eiichi Tabuchi

Position and behavioral modulation of synchronization of hippocampal and accumbens neuronal discharges in freely moving rats.

To understand how hippocampal signals are processed by downstream neurons, we analyzed the relative timing between neuronal discharges in simultaneous recordings in the hippocampus and nucleus accumbens of rats performing in a plus maze. In all, 154 pairs of cells (composed of 65 hippocampal and 56 accumbens neurons) were examined during the 1 s period prior to reward delivery. Cross‐correlation analyses over a ±300‐ms window with 10‐ms bins revealed that 108 pairs had at least one significant histogram bin (P < 0.01). The most frequently occurring peaks of hippocampal firing prior to accumbens discharges appeared at latencies from −30–0 ms, corresponding to published values of the latency of the hippocampal pathway to the nucleus accumbens. Other peaks appeared most often at latencies multiples of about 110 ms prior to and after this, corresponding to theta rhythmicity. Since firing synchronization can result from several types of connectivity patterns (such as common inputs), a group of 18 hippocampus‐accumbens pairs was selected as those most likely to have monosynaptic connections. The criterion was the presence of at least one highly significant peak (P < 0.001) at latencies corresponding to field potentials evoked in the accumbens by hippocampal stimulation. A significant peak occurred on all four maze arms for only one of these cell pairs, indicating positional modulation for the others. In addition, behavior dependence of the synchrony between these nucleus accumbens and hippocampus neurons was examined by studying data in relation to three different synchronization points: reward box arrival, box departure, and arrival at the center of the maze. This indicates that the functional connectivity between hippocampal and accumbens neurons was stronger when the rat was near reward areas. Ten of the hippocampal neurons in these 18 cell pairs showed 9‐Hz (theta) rhythmic activity in autocorrelation analyses. Of these 10 cells, cross‐correlograms from eight hippocampal‐accumbens pairs also showed theta rhythmicity. Overall, these results indicate that the synchrony between hippocampus and nucleus accumbens neurons is modulated by spatial position and behavior, and theta rhythm may play an important role for this synchronization. Hippocampus 2000;10:717–728.

Autonomic responses during inhalation of natural fragrance of “Cedrol” in humans

It is well known that odors affect behaviors and autonomic functions. Previous studies reported that some compounds in cedar wood essence induced behavioral changes including sedative effects. In the present study, we analyzed cardiovascular and respiratory functions while subjects were inhaling fumes of pure compound (Cedrol) which was extracted from cedar wood oil. Vaporized Cedrol (14.2+/-1.7 microg/l, 5 l/min) and blank air (5 l/min) were presented to healthy human subjects (n=26) via a face mask, while ECGs, heart rate (HR), systolic blood pressure (SBP), diastolic BP (DBP), and respiratory rates (RR) were monitored. Statistical analyses indicated that exposure to Cedrol significantly decreased HR, SBP, and DBP compared to blank air while it increased baroreceptor sensitivity. Furthermore, respiratory rate was reduced during exposure to Cedrol. These results, along with the previous studies reporting close relationship between respiratory and cardiovascular functions, suggest that these changes in respiratory functions were consistent with above cardiovascular alterations. Spectral analysis of HR variability indicated an increase in high frequency (HF) component (index of parasympathetic activity), and a decrease in ratio of low frequency to high frequency components (LF/HF) (index of sympathovagal balance) during Cedrol inhalation. Furthermore, Cedrol inhalation significantly decreased LF components of both SBP and DBP variability, which reflected vasomotor sympathetic activity. Taken together, these patterns of changes in the autonomic parameters indicated that Cedrol inhalation induced an increase in parasympathetic activity and a reduction in sympathetic activity, consistent with the idea of a relaxant effect of Cedrol.

Magnetic resonance imaging and histologic evidence of postoperative back muscle injury in rats.

Study Design. Postoperative back muscle injury was evaluated in rats by magnetic resonance imaging and histologic analyses. Objective. To compare the magnetic resonance imaging manifestation of back muscle injury with the histologic findings in rats and to subsequently clarify the histopathologic appearance of the high intensity regions on T2-weighted images in human postoperative back muscles. Summary of Background Data. In a previous study, it was found that the signal intensity on T2-weighted images of the postoperative back muscles was increased in patients who had postsurgical lumbar muscle impairment, especially in those with a prolonged surgery duration. However, the specific histopathologic changes that cause the high signal intensity on T2-weighted images remain unclear. Methods. Rats were divided into three groups: sham operation group, 1-hour retraction group, and 2-hour retraction group. Magnetic resonance imaging and histology of the multifidus muscles were examined before surgery and at 2, 7, and 21 days after surgery. Results. T2-weighted imaging was more useful than T1-weighted imaging to estimate back muscle injury. The high signal intensity of the multifidus muscles on T2-weighted images remained 21 days after surgery only in the 2-hour retraction group. Histologically, the regeneration of the multifidus muscles was complete at 21 days after surgery in the 1-hour retraction group, but the regenerated muscle fibers in the 2-hour retraction group had a small diameter, and the extracellular fluid space remained large. Conclusion. The high signal intensity on T2-weighted images of the postoperative multifidus muscles in the regenerative phase may be due to an increased extracellular space and incomplete muscle fiber regeneration.

Lesions of the medial shell of the nucleus accumbens impair rats in finding larger rewards, but spare reward-seeking behavior.

The goal of this study was to help better understand the importance of the nucleus accumbens (Nacc) in the processing of position and reward value information for goal-directed orientation behaviors. Sixteen male Long-Evans rats, under partial water deprivation, were trained in a plus-maze to find water rewards in the respective arms which were lit in pseudo-random sequence (training trials). Each day one reward arm was selected to deliver six drops of water (at 1 s intervals) the others provided only one drop per visit. After 32 visits, probe trials were intermittently presented among training trials. Here, all four arms were lit and offered the previously assigned reward. The rats rapidly learned to go to the highly rewarded arm. Six trained rats were given bilateral electrolytic lesions in the Nacc shell, two others had unilateral lesions and eight had sham operations (with approved protocols). Field potentials evoked by fornix stimulation were recorded in lesion electrodes to guide placements. Only the lesioned rats showed significant impairments (P<0.05) in selecting the greater reward on probe trials. However on training trials, lesioned (and sham-operated) rats made only rare errors. While the motivation to drink and the capacity for cue-guided goal-directed orientation behavior was spared, lesioned rats were impaired in learning the location of the larger reward. The accumbens lesions apparently impaired integration of position and reward value information, consistent with anatomical and electrophysiological data showing the convergence of hippocampal, amygdalar, ventral tegmental area (VTA) and prefrontal cortical inputs there.

Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring

It has been reported that many types of stresses, which caused physiological and psychological alterations in dams as prenatal maternal stress, affected behavioral and emotional traits of their offspring. However, effects of environmental temperature changes, which induce various stress responses in both animals and humans, have not been assessed as prenatal maternal stress. Repeated cold stress (RCS) is a type of chronic cold stress in which environmental temperature changes rapidly and frequently several times within a day. In the present study, to investigate effects of chronic maternal stress by the RCS on behavioral and emotional development of the rat offspring (prenatal RCS rats), the RCS stress was loaded to pregnant rats between day 9 and 19 after fertilization. The prenatal RCS rats showed similar locomotor activity in an open field to control rats that were borne by non-stressed pregnant rats. On the other hand, the prenatal RCS rats showed significantly higher startle responses than the control rats in a light enhanced startle paradigm. However, treatment of diazepam decreased the startle responses in the prenatal RCS rats to the same degree as those in the control rats. The results indicated that prenatal RCS affected emotional development of the rat offspring, but not locomotor activity. Comparison of the present results with the previous studies suggests that there might be unknown common mechanisms among different prenatal maternal stresses that induce similar behavioral developmental alteration.

Neurons in hippocampal afferent zones of rat striatum parse routes into multi-pace segments during maze navigation.

Hippocampal ‘place’ neurons discharge when rats occupy specific regions within an environment. This finding is a cornerstone of the theory of the hippocampus as a cognitive map of space. But for navigation, representations of current position must be implemented by signals concerning where to go next, and how to get there. In recordings in hippocampal output structures associated with the motor system (nucleus accumbens and ventromedial caudate nucleus) in rats solving a plus‐maze, neurons fired continuously from the moment the rat left one location until it arrived at the next goal site, or at an intermediate place, such as the maze centre. While other studies have shown discharges during reward approach behaviours, this is the first demonstration of activity corresponding to the parsing of complex routes into sequences of movements between landmarks, similar to the lists of instructions we often employ to communicate directions to follow between points on a map. As these cells fired during a series of several paces or re‐orientation movements, perhaps this is homologous to ‘chunking’. The temporal overlaps in the activity profiles of the individual neurons provide a possible substrate to successively trigger movements required to arrive at the goal. These hippocampally informed, and in some cases, spatially selective responses support the view of the ventral striatum as an interface between limbic and motor systems, permitting contextual representations to have an impact on fundamental action sequences for goal‐directed behaviour.

Anticipatory reward signals in ventral striatal neurons of behaving rats

It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of ‘Actor–Critic’ models of trial‐and‐error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model’s adequacy for VS responses to multiple rewards in rats. The respective arms of a plus‐maze provided rewards of varying magnitudes; multiple rewards were provided at 1‐s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor‐related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward‐prediction profiles during reward consumption due to a temporal‐order signal introduced to reproduce accurate timing in dopaminergic reward‐prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal‐order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD‐learning architecture where different groups of neurons participate in solving the task based on varied input information.

Effects of D2 dopamine receptor agonist and antagonist on brain activity in the rat assessed by functional magnetic resonance imaging

The effects of D2 dopamine receptor agonist, bromocriptine (BROMO), and antagonist, haloperidol (HPD), on brain activity were investigated in rats by functional magnetic resonance imaging. T2*-weighted signal intensity was increased in the hypothalamus at 120 min after acute administration of BROMO, and in the ventral posterior and dorsomedial nuclei of the thalamus from 30 to 120 min. In contrast, the signal intensity was decreased in the caudate-putamen at 30 min after acute administration of HPD, in the hypothalamus from 30 to 60 min, and in the perirhinal cortex at 30 min. After chronic (2 weeks) HPD treatment, acute administration of HPD decreased signal intensity in the caudate-putamen at 60 min, in the hypothalamus at 30 min, the perirhinal cortex from 2 to 120 min, the dorsomedial and ventral posterior nuclei of the thalamus from 2 to 120 min, and the medial nucleus of the amygdala from 60 to 120 min. These results suggest that (1) the D2 receptor agonist increased the activity of the thalamic nuclei and the hypothalamus, while the D2 receptor antagonist suppressed brain activity in the regions where D2 receptors were present, (2) the suppression of brain activity in the thalamic nuclei and the perirhinal cortex by acute HPD administration was enhanced by chronic HPD treatment, and (3) the effects of antipsychotic drugs on the thalamus, amygdala, and perirhinal cortex may be related to their therapeutic efficacy, since clinical improvement in schizophrenic patients appears several days after the start of HPD treatment.

Spatio–temporal dynamics of brain activated regions during drinking behavior in rats

Spatio-temporal dynamics of activated brain areas induced by drinking were investigated and visualized in behaving rats using functional magnetic resonance imaging (fMRI). The rats were trained to drink in the magnet bore, and the images were taken during and after drinking glucose and distilled water. During glucose ingestion, the signal intensity was increased continuously and maximally in the lateral hypothalamic area (LHA) and the ventromedial hypothalamus (VMH). Somewhat less intense activation in the central nucleus of the amygdala (AMc), and transient activation in the piriform cortex and the mediodorsal nucleus of the thalamus were observed. The signal intensities of other regions measured were largely unchanged. During post-ingestive periods, the signals re-increased in the hypothalamic areas and AMc. When water was given, LHA and VMH were similarly activated, however, the signal intensity in the amygdala was not significantly increased. The results indicate that these brain regions are activated differentially during drinking behavior, and that LHA and VMH play a central role in the control of not only feeding but also drinking. The regional activities in LHA and VMH are not principally related to the gustatory sensation, and the reactivation after drinking may be related to satisfaction or post-ingestive nutritional information. Also, the responses of AMc are probably due to reward value difference. To the best of our knowledge, this is the first report of mapping of brain areas using fMRI in behaving rats. The improved method described in this study for collecting fMRI data in behaving animals will be useful for studying functional network during animal behavior.

Hippocampal neuronal damage after transient forebrain ischemia in monkeys

To investigate cerebral injury in the monkey due to transient ischemia, monkeys were each subjected to temporary occlusion of eight (bilateral common carotid, internal and external carotid, and vertebral) major arteries. After 0 (control), 5, 10, 13, 15, and 18 min occlusion, blood flow was restored. The monkeys were sacrificed by perfusion fixation 5 days after the operation, and all brain regions were then histologically examined for ischemic neuronal changes induced by the occlusion. The amplitude of EEG signals from skull and scalp became almost isoelectric within 1-6 min after the onset of occlusion. The EEG signals from the hippocampus were markedly attenuated within 1-4 min, although they did not become completely isoelectric. Blood pressure was significantly increased after 10-min ischemia. Five-min occlusion produced no ischemic neuronal changes except a slight increment of glial cells in the striatum and III, V, and VI layers of the neocortices. After 10- to 15-min occlusion, there were ischemic cell changes restricted exclusively to the CA1 subfield of the hippocampus. Eighteen-min occlusion produced more prominent ischemic neuronal damage in the CA1 subfield of the hippocampus, but ischemic neuronal damage was no longer confined to the hippocampus. These results suggest that only the CA1 subfield of the monkey hippocampus could be damaged by mild ischemic insult. We demonstrate that the limited lesion of the hippocampus, especially the CA1 subfield, after 10- to 15-min occlusion of eight arteries in the monkey, produces a model equivalent to human amnesia caused by transient ischemic insult.