Medial auditory thalamic stimulation as a conditioned stimulus for eyeblink conditioning in rats

The neural pathways that convey conditioned stimulus (CS) information to the cerebellum during eyeblink conditioning have not been fully delineated. It is well established that pontine mossy fiber inputs to the cerebellum convey CS-related stimulation for different sensory modalities (e.g., auditory, visual, tactile). Less is known about the sources of sensory input to the pons that are important for eyeblink conditioning. The first experiment of the current study was designed to determine whether electrical stimulation of the medial auditory thalamic nuclei is a sufficient CS for establishing eyeblink conditioning in rats. The second experiment used anterograde and retrograde tract tracing techniques to assess neuroanatomical connections between the medial auditory thalamus and pontine nuclei. Stimulation of the medial auditory thalamus was a very effective CS for eyeblink conditioning in rats, and the medial auditory thalamus has direct ipsilateral projections to the pontine nuclei. The results suggest that the medial auditory thalamic nuclei and their projections to the pontine nuclei are components of the auditory CS pathway in eyeblink conditioning.     

DNA methylation and behavioral changes induced by neonatal spinal transection

Although the importance of epigenetic mechanisms in behavioral development has been gaining attention in recent years, research has largely focused on the brain. To our knowledge, no studies to date have investigated epigenetic changes in the developing spinal cord to determine the dynamic manner in which the spinal epigenome may respond to environmental input during behavioral development. Animal studies demonstrate that spinal cord plasticity is heightened during early development, is somewhat preserved following neonatal transection, and that spinal injured animals are responsive to sensory feedback. Because epigenetic alterations have been implicated in brain plasticity and are highly responsive to experience, these alterations are promising candidates for molecular substrates of spinal plasticity as well. Thus, the current study investigated behavioral changes in the development of weight-bearing locomotion and epigenetic modifications in the spinal cord of infant rats following a neonatal low-thoracic spinal transection or sham surgery on postnatal day (P)1. Specifically, global levels of methylation and methylation status of the brain-derived neurotrophic factor (Bdnf) gene, a neurotrophin heavily involved in both CNS and behavioral plasticity, particularly in development, were examined in lumbar tissue harvested on P10 from sham and spinal-transected subjects. Behavioral results demonstrate that compared to shams, spinal-transected subjects exhibit significantly reduced partial-weight bearing hindlimb activity. Molecular data demonstrate group differences in global lumbar methylation levels as well as exon-specific group differences in Bdnf methylation. This study represents an initial step toward understanding the relationship between epigenetic mechanisms and plasticity associated with spinal cord and locomotor development.     

The role of the anterodorsal thalami nuclei in the regulation of adrenal medullary function, beta-adrenergic cardiac receptors and anxiety responses in maternally deprived rats under stressful conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac beta-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac beta-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac beta-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial beta-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.     

When good pain turns bad

Classically, pain is viewed as being mediated solely by neurons. However, recent research has shown that activated glial cells (astrocytes and microglia) within the spinal cord amplify pain. These nonneuronal cells play a major role in the creation and maintenance of pathological pain. Glia become activated by immune challenges (viral or bacterial infection) and by substances released by neurons within the pain pathway. Activated glia amplify pain by releasing proinflammatory cytokines. Taken together, research findings suggest a novel approach to human pain control that targets glia. In addition, it is likely that such glial-neuronal interactions are not unique to pain, but rather reflect a general rule of sensory processing.     

The cerebellum in maintenance of a motor skill: a hierarchy of brain and spinal cord plasticity underlies H-reflex conditioning

Operant conditioning of the H-reflex, the electrical analog of the spinal stretch reflex, is a simple model of skill acquisition and involves plasticity in the spinal cord. Previous work showed that the cerebellum is essential for down-conditioning the H-reflex. This study asks whether the cerebellum is also essential for maintaining down-conditioning. After rats decreased the soleus H-reflex over 50 d in response to the down-conditioning protocol, the cerebellar output nuclei dentate and interpositus (DIN) were ablated, and down-conditioning continued for 50-100 more days. In naive (i.e., unconditioned) rats, DIN ablation itself has no significant long-term effect on H-reflex size. During down-conditioning prior to DIN ablation, eight Sprague-Dawley rats decreased the H-reflex to 57% (+/-4 SEM) of control. It rose after ablation, stabilizing within 2 d at about 75% and remaining there until approximately 40 d after ablation. It then rose to approximately 130%, where it remained through the end of study 100 d after ablation. Thus, DIN ablation in down-conditioned rats caused an immediate increase and a delayed increase in the H-reflex. The final result was an H-reflex significantly larger than that prior to down-conditioning. Combined with previous work, these remarkable results suggest that the spinal cord plasticity directly responsible for down-conditioning, which survives only 5-10 d on its own, is maintained by supraspinal plasticity that survives approximately 40 d after loss of cerebellar output. Thus, H-reflex conditioning seems to depend on a hierarchy of brain and spinal cord plasticity to which the cerebellum makes an essential contribution.     

Neuroprotective Effects of Testosterone on Regenerating Spinal Cord Motoneurons in Rats

Degeneration in the CNS and peripheral nervous system consists of degradation and phagocytosis of axons and their myelin sheath distal to the site of injury. Testosterone is a gonadal sex steroid hormone that plays an important role in CNS development. One of the lesser-known testosterone actions is neuroprotection. In the present study, the authors investigated the neuroprotectective effect of intracerebral ventricular injection of testosterone on the number of spinal motoneurons after sciatic nerve crush. In all, 32 male Wistar rats were divided to 4 groups (control, compression, compression + castration, compression + testosterone injections; n = 8). Four weeks after compression the lumber segments of spinal cord were sampled, processed, sectioned serially, and stained with toluidine blue (pH = 4.65) by using steriological quantitative technique (physical dissector), the number of alpha motoneurons in the right ventral horns of spinal cord were counted and compared between groups. Statistical analyses showed that testosterone injections (1μl icv, 4 times, 1 week interval between injections) significantly (p < .05) reduced neuronal damage. These results indicated that testosterone has an obvious neuroprotective effect on lumbar spinal motoneurons.     

Spinal and locus coeruleus noradrenergic lesions abolish the analgesic effects of 5-methoxy-N,N-dimethyltryptamine

Two experiments were performed on Sprague-Dawley rats to study the effects of noradrenaline and 5-hydroxytryptamine depletion upon the antinociceptive effects of acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) administration. 6-Hydroxydopamine-induced lesions following microinjections to either the locus coeruleus or the spinal cord (lumbar) abolished completely 5-MeODMT-induced analgesia in the tail-flick, hot-plate, and shock titration tests whereas 5,7-dihydroxytryptamine-induced lesions of the nucleus raphe magnus and the lumbar spinal cord attenuated 5-MeODMT analgesia in the tail-flick and shock titration tests. Thus, the experiments serve to demonstrate an important interaction between descending noradrenergic and serotonergic pathways, possibly at a spinal locus.     

Human lumbar cord circuitries can be activated by extrinsic tonic input to generate locomotor-like activity

We have demonstrated that non-patterned electrical stimulation of the lumbar cord can induce stepping-like activity in the lower limbs of complete spinal cord injured individuals. This result suggested the existence of a human lumbar locomotor pattern generator, which can convert a tonic input to a rhythmic motor output. We have studied the human lumbar cord in isolation from supraspinal input but under extrinsic tonic input delivered by spinal cord stimulation. Large-diameter afferents within the posterior roots are directly depolarized by the electrical stimulation. These afferents project to motoneurons as well as to lumbar interneurons involved in the motor control of lower limbs. Stimulation at 25-50 Hz can elicit rhythmic alternating flexion/extension movements of the lower limbs in supine individuals. Reducing the tonic input frequency to 5-15 Hz initiates lower limb extension. Epidural stimulation applied during manually assisted treadmill stepping in complete spinal cord injured persons immediately increases the central state of excitability of lumbar cord networks and enhances stepping-like functional motor outputs. Sustained, non-patterned tonic input via the posterior roots can activate human lumbar cord networks. Pattern generating configurations of these multifunctional circuitries can be set-up depending on the stimulation parameters and particularly on the input frequency.     

Cross over of forebrain and brainstem neuronal projections to spinal cord sympathetic preganglionic neurons in the rat

Neuronal inputs from the forebrain and the brainstem to sympathetic preganglionic neurons in the spinal cord were investigated by the transneuronal retrograde tracing technique using pseudorabies virus in intact and brainstem-lesioned rats. After unilateral subcutaneous viral inoculations into the hind limb of intact rats, infected neurons were then visualized by immunostaining. At 3.5 days after inoculation, infected neurons appeared in the thoracic (T10) intermediolateral (IML) cell column. On the 4th day, infected neurons were present in the C1, A5, A6, A7 catecholamine cell groups and the rostral ventromedial medulla (RVMM). On the 5th day, viral labeling was seen in the hypothalamic paraventricular and arcuate nuclei and the lateral hypothalamic area. In all of these nuclei, the infected cells appeared bilaterally. However, the appearance of virus-labeled cells in these nuclei was unilateral following unilateral coronal sections between the medulla and the spinal cord (depending on the side of hemisection, but not on the site of virus inoculation). Midsagittal sections throughout the entire medulla oblongata did not alter the topographical pattern of virus-infected neurons in the forebrain or the brainstem. These findings indicate that descending fibers to the spinal neurons may not cross over in the lower brainstem but that they decussate within the spinal cord.     

Limb-specific emotional modulation of cervical spinal cord neurons

Emotional stimuli receive prioritized attentional and motoric processing in the brain. Recent data have indicated that emotional stimuli enhance activity in the cervical spinal cord as well. In the present study, we used fMRI to investigate the specificity of this emotion-dependent spinal cord activity. We examined whether the limb depicted in a passively viewed image (upper vs. lower) differentially influenced activity in the cervical segments that innervate the upper limbs, and whether this effect was enhanced by emotion. Participants completed four fMRI runs: neutral–upper limb, neutral–lower limb, negative–upper limb, and negative–lower limb. The results indicated main effects of limb and emotion, with upper limbs and negative stimuli eliciting greater activity than lower limbs and neutral stimuli, respectively. For upper-limb runs, negative stimuli evoked more activity than did neutral stimuli. Additionally, negative stimuli depicting upper limbs produced stronger responses than did negative stimuli depicting lower limbs. These results suggest that emotional stimuli augment limb-specific responses in the spinal cord.     

Human feelings: why are some more aware than others?

A recent article reports that human perception of heartbeat timing is mediated by right (non-dominant) anterior insular cortex, and that the activity and the size of this region is directly correlated with individuals' subjective awareness of inner body feelings and emotionality. These results support the somatic-marker hypothesis of consciousness (a modern successor to the James-Lange theory of emotion) and the neuroanatomical concept that human awareness is based on a phylogenetically distinct interoceptive pathway.     

Ablation of cerebellar nuclei prevents H-reflex down-conditioning in rats

While studies of cerebellar involvement in learning and memory have described plasticity within the cerebellum, its role in acquisition of plasticity elsewhere in the CNS is largely unexplored. This study set out to determine whether the cerebellum is needed for acquisition of the spinal cord plasticity that underlies operantly conditioned decrease in the H-reflex, the electrical analog of the spinal stretch reflex. Rats in which the cerebellar output nuclei dentate and interpositus (DIN) had been ablated were exposed for 50 d to the H-reflex down-conditioning protocol. DIN ablation, which in itself had no significant long-term effect on H-reflex size, entirely prevented acquisition of a smaller H-reflex. Since previous studies show that corticospinal tract (CST) transection also prevents down-conditioning while transection of the rubrospinal tract and other major descending tracts does not, this result implies that DIN output that affects cortex is essential for generation of the CST activity that induces the spinal cord plasticity, which is, in turn, directly responsible for the smaller H-reflex. The result extends the role of the cerebellum in learning and memory to include participation in induction of plasticity elsewhere in the CNS, specifically in the spinal cord. The cerebellum might simply support processes in sensorimotor cortex or elsewhere that change the spinal cord, or the cerebellum itself might undergo plasticity similar to that occurring with vestibulo-ocular reflex (VOR) or eyeblink conditioning.     

小学学习不良儿童言语交际策略理解水平及其发展特点

采用言语交际策略认知结构访谈故事情境,考察了小学3~6年级学习不良儿童言语交际策略理解水平的发展以及言语行为对其策略理解的影响。被试为两所普通小学儿童,其中学习不良117名,一般儿童124名。结果表明：学习不良儿童言语交际策略理解水平在总体发展上显著落后于一般儿童,但滞后仅存在于意图表达间接程度较高的暗示策略上。其次,在不同言语行为类别上发展趋势不同。对于礼貌请求策略,学习不良儿童不存在显著年级差异,而一般儿童则表现出随年级的增长而逐步提高的趋势;对于委婉应答策略,学习不良儿童存在显著的年级差异。     

触觉的情绪功能及其神经生理机制

触觉是个体探知外部世界的重要感觉通道, 其情绪功能在维系社会联结、促进人际沟通等方面具有重要作用。触觉的情绪功能一方面表现为通过触觉动作本身直接传递情绪信息, 另一方面则是通过增强注意和锐化社会评价的方式促进个体对跨通道情绪信息的加工。神经生理学研究发现, 触觉情绪信息由无髓鞘C纤维介导, 经脊髓丘脑束通路投射于岛叶(头面部触觉情绪信息的传导路径尚不明确), 并在杏仁核、内侧前额叶、后颞上沟等“社会脑”网络的核心区域被精细加工。未来还应对触觉情绪的人际依赖性、文化独特性、操作标准化, 及其在神经水平上与感觉-辨识系统间的关联性与独立性做深入探究。     

Opioid regulation of spinal cord plasticity: evidence the kappa-2 opioid receptor agonist GR89696 inhibits learning within the rat spinal cord

Spinal cord neurons can support a simple form of instrumental learning. In this paradigm, rats completely transected at the second thoracic vertebra learn to minimize shock exposure by maintaining a hindlimb in a flexed position. Prior exposure to uncontrollable shock (shock independent of leg position) disrupts this learning. This learning deficit lasts for at least 24h and depends on the NMDA receptor. Intrathecal application of an opioid antagonist blocks the expression, but not the induction, of the learning deficit. A comparison of selective opioid antagonists implicated the kappa-opioid receptor. The present experiments further explore how opioids affect spinal instrumental learning using selective opioid agonists. Male Sprague-Dawley rats were given an intrathecal injection (30 nmol) of a kappa-1 (U69593), a kappa-2 (GR89696), a mu (DAMGO), or a delta opioid receptor agonist (DPDPE) 10 min prior to instrumental testing. Only the kappa-2 opioid receptor agonist GR89696 inhibited acquisition (Experiment 1). GR89696 inhibited learning in a dose-dependent fashion (Experiment 2), but had no effect on instrumental performance in previously trained subjects (Experiment 3). Pretreatment with an opioid antagonist (naltrexone) blocked the GR89696-induced learning deficit (Experiment 4). Administration of GR89696 did not produce a lasting impairment (Experiment 5) and a moderate dose of GR89696 (6 nmol) reduced the adverse consequences of uncontrollable nociceptive stimulation (Experiment 6). The results suggest that a kappa-2 opioid agonist inhibits neural modifications within the spinal cord.     

Recovery of Locomotion in Monkeys With Spinal Cord Lesions

This study reanalyzes kinematically (via film) the pre- and postoperative locomotor behavior of 4 of the 10 monkeys with partial spinal cord lesions (T8) briefly described by Eidelberg, Walden, and Nguyen (1981). The behavior of the remaining 6 monkeys is qualitatively described. The analysis reveals that 5 of the animals initially exhibited unilateral hind limb stepping. Hind and forelimb cycle durations often differed postoperatively; the hind limbs commonly showed increased values, whereas forelimb cycle durations were reduced: ipsilateral interlimb phase values were usually inconsistent. A review of prior studies of primate spinal cord lesions indicates that sparing of the ventrolateral quadrant may not be essential for locomotor recovery (cf. Eidelberg, Walden, & Nguyen, 1981). Furthermore, this review as well as the kinematic analysis indicates that primates with very significant spinal lesions can stilI exhibit locomotor movements. Thus, although the primate's spinal cord seems less able than other mammals' to readily organize locomotor movements (Eidelberg, Walden, & Nguyen, 1981), the total absence of stepping in primates with completely transected cords is unexpected and warrants further research.     

Recovery of Locomotion in Monkeys with Spinal Cord Lesions

This study reanalyzes kinematically (via film) the pre- and postoperative locomotor behavior of 4 of the 10 monkeys with partial spinal cord lesions (T8) briefly described by Eidelberg, Walden, and Nguyen (1981). The behavior of the remaining 6 monkeys is qualitatively described. The analysis reveals that 5 of the animals initially exhibited unilateral hind limb stepping. Hind and forelimb cycle durations often differed postoperatively; the hind limbs commonly showed increased values, whereas fore-limb cycle durations were reduced. Ipsilateral interlimb phase values were usually inconsistent.

A review of prior studies of primate spinal cord lesions indicates that sparing of the ventrolateral quadrant may not be essential for locomotor recovery (cf. Eidelberg, Walden, and Nguyen, 1981). Furthermore, this review as well as the kinematic analysis indicates that primates with very significant spinal lesions can still exhibit locomotor movements. Thus, although the primate's spinal cord seems less able than other mammals' to readily organize locomotor movements (Eidelberg, Walden, & Nguyen, 1981), the total absence of stepping in primates with completely transected cords is unexpected and warrants further research.     

Anticipatory threat and physical danger trait anxiety: A signal-detection analysis of effects on autonomic responding

The method of Signal-Detection Theory (SDT) was applied to the analysis of autonomic data in two experiments. In the first, apprehension surrounding the administration of loud tones was induced through preliminary information; in the second, it was increased by selecting subjects scoring high on a physical-danger trait anxiety scale. Despite enhanced autonomic reactivity, those in the first study who were led to believe that the tones would be extremely disturbing subsequently rated them as less disturbing than did their counterparts who were given comparatively benign expectations. The signal-detection analysis of heart rate and skin conductance suggested enhanced “preparedness of response” among the high-threat subjects; given the diminished subjective ratings, increased response readiness at the autonomic level may have reflected physiological activity assuaging subjective aversiveness of the tones. Contrary to the first study, the psychometrically designated threatened group in the second experiment produced both greater autonomic reactivity along with elevated subjective ratings of disturbance. The SDT analysis provided evidence of greater autonomic sensitivity to noxious stimulus properties. Results were discussed in terms of their implications for theories of anxiety; the comparative utilites of signal-detection theory and conventional methods of autonomic-response scoring were elaborated.     

Intermittent exposure to social defeat and open-field test in rats: acute and long-term effects on ECG,body temperature and physical activity

This study investigated the effects of exposure to an intermittent homotypic stressor on: (i) habituation of acute autonomic responsivity (i.e. cardiac sympathovagal balance and susceptibility to arrhythmias), and (ii) circadian rhythmicity of heart rate, body temperature, and physical activity. After implantation of a transmitter for the radiotelemetric recording of electrocardiogram (ECG), body temperature and physical activity, adult male rats (Rattus norvegicus, Wild Type Groningen strain) were repeatedly exposed (10 consecutive times, on alternate days) to either a social stressor (defeat by a con-specific, n = 15) or an open-field, control challenge (transfer to a new cage; n = 8). ECGs, body temperature and physical activity were continuously recorded in baseline, test and recovery periods (each lasting 15 min), at the 1st and 10th episodes of both defeat and open-field challenge. The circadian rhythms of heart rate, body temperature and physical activity were monitored before (5 days), during (16 days) and after (21 days) the intermittent stress protocol. This study indicates that there is no clear habituation of either acute cardiac autonomic responsivity (as estimated by means of time-domain indexes of heart rate variability) or arrhythmia occurrence to a brief, intermittent, homotypic challenge, regardless of the nature of the stressor (social or non-social). On the other hand, rats exposed to social challenge also failed to show adaptation of acute temperature and activity stress responsiveness, whereas rats facing open-field challenge developed habituation of activity and sensitization of temperature responses. Repeated social challenge produced remarkable reductions of the heart rate circadian rhythm amplitude (this effect being significantly greater than that produced by intermittent open-field), but only minor changes in the daily rhythms of body temperature and physical activity.     

Identification of a cortical site for stress-induced cardiovascular dysfunction

The evidence indicating that the insular cortex is a likely candidate to mediate stress-induced cardiovascular responses is reviewed. Both neuroanatomical and electrophysiological investigations demonstrate that the insular cortex receives an organized representation of visceral information. In addition, the insular cortex also receives highly processed association cortex information. The insular cortex is also highly interconnected with many subcortical limbic and autonomic regions. This combination of sensory input and limbic/autonomic connectivity would be necessary to permit the insular cortex to be a critical site for the integration of emotional and autonomic responses. Stimulation of the insular cortex elicits specific cardiovascular and autonomic responses from discrete sites. Phasic stimulation entrained to the cardiac cycle is even capable of causing severe arrhythmias. The efferent pathways and some of the neurotransmitter mechanisms have determined. It appears that the lateral hypothalamic area is the primary site of synapse for autonomic responses originating in the insular cortex and this information is relayed by NMDA glutamatergic receptors and modulated by neuropeptides including neuropeptide Y, neurotensin, leu-enkephalin and dynorphin. Finally, a rat stroke model, which includes the insular cortex in the infarct region indicates that disruption of the insula can produce substantial cardiac and autonomic abnormalities, which might be similar to those produced by stress. Some of the chronic neurochemical changes, including increases in opioids, neuropeptide Y and neurotensin in the central nucleus of the amygdala, which might be mediating these cardiovascular disturbances, have been determined.