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Age effect on motor recovery in a post-acute animal stroke model.

Male Fischer 344 rats aged 3, 6, 12, 18 and 24 months were trained to walk on a narrow beam, then lesioned in the right hindlimb sensorimotor cortex by photothrombosis. Motor performance was measured daily for 60 days using a 7-point rating scale from which deficit scores were calculated. Tissue analysis included lesion volume measurement after Nissl staining. Animals aged 3 and 6 months fully recovered by day 10 and 31, respectively. Animals aged 18 months acquired significant neurological impairment that persisted greater than 60 days. Deficit scores were significantly greater than in groups aged 12, 6 and 3 months. Degenerative morbidity and mortality confounded behavioral study of animals aged 24 months. The duration of neurological impairment after photochemical sensorimotor cortex lesion increased with age. Animals aged 18 months at lesion acquired the greatest chronic impairment. This aged post-acute animal model is clinically relevant to stroke rehabilitation.

Acute Disease↗

Convergence of neural systems processing stimulus associations and coordinating motor responses.

A sensory-sensory learning paradigm was used to measure neural changes in humans during acquisition of an association between an auditory and visual stimulus. Three multivariate partial least-squares (PLS) analyses of positron emission tomography data identified distributed neural systems related to (i) processing the significance of the auditory stimulus, (ii) mediating the acquisition of the behavioral response, and (iii) the spatial overlap between these two systems. The system that processed the significance of the tone engaged primarily right hemisphere regions and included dorsolateral prefrontal cortex, putamen, and inferior parietal and temporal cortices. Activity changes in left occipital cortex were also identified, most likely reflecting the learned expectancy of the upcoming visual event. The system related to behavior was similar to that which coded the significance of the tone, including dorsal occipital cortex. The PLS analysis of the concordance between these two systems showed substantial regional overlap, and included occipital, dorsolateral prefrontal, and limbic cortices. However, activity in dorsomedial prefrontal cortex was strictly related to processing the auditory stimulus and not to behavior. Taken together, the PLS analyses identified a system that contained a sensory-motor component (comprised of occipital, temporal association and sensorimotor cortices) and a medial prefrontallimbic component, that as a group simultaneously embodied the learning-related response to the stimuli and the subsequent change in behavior.

Acoustic Stimulation↗

Dynamic behaviors of growth cones extending in the corpus callosum of living cortical brain slices observed with video microscopy.

During development, axons of the mammalian corpus callosum must navigate across the midline to establish connections with corresponding targets in the contralateral cerebral cortex. To gain insight into how growth cones of callosal axons respond to putative guidance cues along this CNS pathway, we have used time-lapse video microscopy to observe dynamic behaviors of individual callosal growth cones extending in living brain slices from neonatal hamster sensorimotor cortex. Crystals of the lipophilic dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) were inserted into the cortex in vivo to label small populations of callosal axons and their growth cones. Subsequently, 400 microns brain slices that included the injection site, the corpus callosum, and the target cortex were placed in culture and viewed under low-light-level conditions with a silicon-intensified target (SIT) camera. Time-lapse video observations revealed striking differences in growth cone behaviors in different regions of the callosal pathway. In the tract, which is defined as the region of the callosal pathway from the injection site to the corresponding target cortex, growth cones advanced rapidly, displaying continual lamellipodial shape changes and filopodial exploration. Forward advance was sometimes interrupted by brief pauses or retraction. Growth cones in the target cortex had almost uniform compact shapes that were consistently smaller than those in the tract. In cortex, axons adhered to straight radial trajectories and their growth cones extended at only half the speed of those in the tract. Growth cones in subtarget regions of the callosum beneath cortical targets displayed complex behaviors characterized by long pauses, extension of transitory branches, and repeated cycles of collapse, withdrawal, and resurgence. Video observations suggested that extension of axons into cortical targets could occur by interstitial branching from callosal axons rather than by turning behaviors of the primary growth cones. These results suggest the existence of guidance cues distinct for each of these callosal regions that elicit characteristic growth cone behaviors.

Animals↗

Mood, performance, and pain sensitivity: changes induced by food constituents.

We examined the behavioral effects of the dietary constituents tryptophan and tyrosine on human mood, sensorimotor performance and pain sensitivity. Tryptophan and tyrosine are neurotransmitter precursors present in varying amount in protein-containing foods. Tryptophan (50 mg/kg) increased subjective drowsiness and fatigue but unlike many hypnotics did not impair sensorimotor performance. Tryptophan also decreased human pain sensitivity in a manner that was more specific than certain analgesic drugs.

Adolescent↗

Distinct temporal activity patterns in the rat M1 and red nucleus during skilled versus unskilled limb movement.

The mammalian motor system contains multiple interconnected supraspinal networks, but little is known about their relative roles in producing different movements and behaviors, particularly given their apparently fused activity in primates. We tested whether the task context, as well as using a phylogenetically older mammal, rats, could distinguish the separate contributions of these networks. We obtained simultaneous multi-single neuron recordings from the forelimb motor cortex and magnocellular red nucleus as rats performed two contextually different, but kinematically similar, forelimb reach-like tasks: highly learned, skilled reaching for food through a narrow slot, a task requiring extensive training, versus the swing phases of treadmill locomotion. In both the M1 and the mRN, large subpopulations of neurons peaked in their spike firing rates near the onset and the end of the swing phase during treadmill locomotion. In contrast, neural subgroups in the two areas displayed different temporal sequences of activity during the skilled reaching task. In the mRN, the majority of task-modulated neurons peaked in their firing rate in the middle of the reach when the rat was preparing to project the arm through the slot, whereas large subgroups of M1 neurons displayed elevated firing rates during the initial and terminal phases of the reach. These results suggest that motor-behavioral context can alter the degree of overlapping activity in different supraspinal sensorimotor networks. Moreover, results for the skilled reaching task in rats may have highlighted a distinct processing role of the rubral complex: adapting natural muscle synergies across joints and limbs to novel task demands, in concert with cortically based learning.

Animals↗

The fine organization of nigro-collicular channels with additional observations of their relationships with acetylcholinesterase in the rat.

The nigro-collicular pathway that links the basal ganglia to the sensorimotor layers of superior colliculus plays a crucial role in promoting orienting behaviors. This connection originating in the pars reticulata and lateralis of the substantia nigra has been shown in rat and cat to be topographically organized. In rat, a functional compartmentalization of the substantia nigra has also been shown reflecting that of the striatum. In light of this, we reinvestigated the topographical arrangement of the nigro-collicular pathway by examining the innervation of each nigral functional zone. We performed small injections of either biocytin or wheatgerm agglutinin conjugated with horseradish peroxidase restricted to identified somatic, visual and auditory nigral zones. Frontally cut sections showed that innervations provided by the three main nigral zones form a mosaic of complementary domains stratified from the stratum opticum to the ventral part of the intermediate collicular layers, with the somatic afferents sandwiched between the visual and the auditory ones. When reconstructed from semi-horizontal sections, nigral innervations organized in the form of a honeycomb-like array composed of 100 cylindrical modules covering three-quarters of the collicular surface. Such a modular architecture is reminiscent of the acetylcholinesterase lattice we previously described in rat intermediate collicular layers. In the enzyme lattice, the surroundings of the cylindrical modules are composed of a mosaic of dense and diffuse enzyme subdomains. Thus, we compared the distribution of the overall nigral projection and of its constituent channels with the acetylcholinesterase lattice. The procedure combined axonal labelling with histochemistry on single sections for acetylcholinesterase activity. The results demonstrate that the overall nigral projection overlaps the acetylcholinesterase lattice and its constituent channels converge with either the dense or the diffuse enzyme subdomains. The stereometric arrangement of the nigro-collicular pathway is suggestive of an architecture promoting the selection of collicular motor programs for different classes of orienting behavior.

Acetylcholine↗

Central processes for the multiparametric control of arm movements in primates.

Recent single-unit recording studies have clarified how multiple parameters of movement are signaled by individual cortical and cerebellar neurons, and also that multiple coordinate frames are utilized. Cognitive processes also modulate the firing of these neurons. The various signals and coordinate systems vary in time and evolve throughout a behavioral sequence, consistent with the demands of the task and the required sensorimotor transformations.

Animals↗

[Spectral analysis of the effects of nomifensine on bioelectric activity of the rat brain].

The influence of nomifensine on bioelectrical activity of sensorimotor cortex, dorsal hippocamp and lateral hypothalamus in conscious rats in free behavior was studied. The pharmacological and EEG analysis of nomifensine action on EEG power spectra by Fourier technique was measured. It was established that nomifensine evoked an increase and stabilization of the dominant peak in EEG spectra in the left and right cortex and in the left hippocamp, while in the other ranges of frequency a decrease was observed. The effects on hypothalamus was opposite--EEG power spectra decreased in all the ranges. The authors conclude that nomifensine evokes higher level of wakefulness, vigilance of the animals. This is likely to underlie neurophysiological mechanisms of optimal behavior due to stimulants of CNS, including nomifensine.

Animals↗

A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.

BACKGROUND: As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus. METHODS: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed. RESULTS: Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype. CONCLUSIONS: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.

Amphetamine↗

Motor-skill learning-associated gene regulation in the striatum: effects of cocaine.

Psychostimulant-induced molecular changes in cortico-basal ganglia-cortical circuits play a critical role in addiction and dependence. These changes include alterations in gene regulation particularly in projection neurons of the sensorimotor striatum. We previously showed that cocaine-induced gene regulation in such neurons is dependent on the behavior performed during drug action. Rats trained on a running wheel under the influence of cocaine for 4 days subsequently displayed greater c-fos induction by cocaine than untrained controls. This effect was selective for the sensorimotor striatum, which is known to mediate forms of motor learning. In the present study, we investigated whether this enhanced cellular responsiveness was associated with learning of wheel running or with prolonged running (exercising), by assessing c-fos inducibility after 1, 2, or 8 days of training. Wheel training was performed after injection of cocaine (25 mg/kg) or vehicle, and c-fos induction by a cocaine challenge was measured 24 h later. Rats that trained under cocaine (but not vehicle) showed a greater c-fos response in the striatum compared to locked-wheel controls. This effect was present after the 1-day training, peaked after 2 days, and dissipated by 8 days of training. Similar effects were found for substance P, but not enkephalin, expression. These changes in striatal gene regulation paralleled improvement in wheel running, which was facilitated by cocaine. Thus, these training-induced molecular changes do not appear to represent exercising effects, but may reflect motor learning-associated neuronal changes altered by cocaine. Such cocaine effects may contribute to aberrant motor learning implicated in psychostimulant addiction.

Animals↗

Cocaine alters behavior in the rat fetus.

Changes in motor behavior and sensory responsiveness were characterized in rat fetuses on gestational Day 21 after acute administration of various doses of cocaine. An increase in fetal motor activity was evident in the 3 highest doses (5, 10, and 20 mg/kg). Cocaine-exposed Ss showed reduced facial wiping in behavioral bioassays of cutaneous sensitivity (10 and 20 mg/kg) and chemosensory responsiveness (20 mg/kg). Changes in other behavioral measures indicated that fetuses detected and responded to these stimuli, suggesting that reduced facial wiping was due to a disruption of sensorimotor integration or motor coordination. Study of the fetus in vivo can provide insights into the mechanisms of cocaine's deleterious effects on central nervous system and behavioral development.

Animals↗

Secondary hypoxia following moderate fluid percussion brain injury in rats exacerbates sensorimotor and cognitive deficits.

Human head trauma is frequently associated with respiratory problems resulting in secondary hypoxic insult. To document the behavioral consequences of secondary hypoxia in an established model of traumatic brain injury (TBI), intubated anesthetized animals were subjected to fluid percussion (FP) injury (1.87-2.17 atm) followed by 30 min of either normoxic (TBI-NO, n = 10) or hypoxic (TBI-HY, n = 11; pO2 = 30-40 mm Hg) gas levels. Sham animals (n = 19) underwent all manipulations except for the actual trauma. Animals were tested on various sensorimotor tasks beginning 3 days after FP injury along with cognitive testing on days 22 through 29 posttrauma. The secondary hypoxic insult exacerbated the sensorimotor deficits on beam-walking compared to those animals only receiving trauma. Cognitive impairments were also observed in the TBI-HY group in the hidden platform task compared to FP injury alone. These data indicate that a secondary hypoxic insult exacerbates both sensorimotor and cognitive deficits after TBI. This study provides direct evidence that incidences of hypoxia after brain trauma may potentially result in an increase in neurological deficits for the subpopulation of head injured patients undergoing hypoxic conditions further warranting strict monitoring of these events.

Animals↗

The primate substantia nigra and VTA: integrative circuitry and function.

A substantial amount of research has focused on the midbrain dopamine system and its role in mediating a wide range of behaviors. In diseases in which dopamine function is compromised, patients exhibit a constellation of symptoms suggesting that the dopamine system plays an important role in the integration of several functions. We have shown that there are subgroups of dopamine neurons that receive information from limbic and association areas and project widely throughout cortex and striatum, including motor areas. A dorsal tier of dopamine neurons receive input from the ventral (limbic) striatum and the amygdala and project widely throughout cortex. A more ventrally located group of dopamine cells receives input from both the limbic and association areas of striatum and project widely throughout the striatum including the sensorimotor regions. Through these projections the dopamine system can effect a wide range of behaviors. For the most part, structures of the basal ganglia are thought to be organized in parallel pathways. However, the behaviors affected by basal ganglia disorders can be in part explained by the integrative nature of the dopamine system and its links to motor, limbic, and association areas of the striatum and cortex.

Afferent Pathways↗

Tool use, aye-ayes, and sensorimotor intelligence.

Humans, chimpanzees, capuchins and aye-ayes all display an unusually high degree of encephalization and diverse omnivorous extractive foraging. It has been suggested that the high degree of encephalization in aye-ayes may be the result of their diverse, omnivorous extractive foraging behaviors. In combination with certain forms of tool use, omnivorous extractive foraging has been hypothesized to be linked to higher levels of sensorimotor intelligence (stages 5 or 6). Although free-ranging aye-ayes have not been observed to use tools directly in the context of their extractive foraging activities, they have recently been reported to use lianas as tools in a manner that independently suggests that they may possess stage 5 or 6 sensorimotor intelligence. Although other primate species which display diverse, omnivorous extractive foraging have been tested for sensorimotor intelligence, aye-ayes have not. We report a test of captive aye-ayes' comprehension of tool use in a situation designed to simulate natural conditions. The results support the view that aye-ayes do not achieve stage 6 comprehension of tool use, but rather may use trial-and-error learning to develop tool-use behaviors. Other theories for aye-aye encephalization are considered.

Animals↗

The role of the septohippocampal pathway in the regulation of hippocampal field activity and behavior: analysis by the intraseptal microinfusion of carbachol, atropine, and procaine.

The role of the septohippocampal pathway in the regulation of hippocampal field activity and behavior was assessed using the technique of intraseptal microinfusion of carbachol, atropine, and procaine. The effects of these manipulations were assessed by comparing them with the effects of intraseptal saline control infusions on spontaneously occurring motor behaviors and their correlated hippocampal field activities. In control conditions hippocampal theta field activity, with up to 40% of the total power concentrated in a 1-Hz band around the peak frequency, was recorded only during type 1 voluntary motor behaviors. Hippocampal large-amplitude irregular activity was recorded during type 2 automatic motor behaviors and during immobility. Microinfusion of carbachol into the MS/vDBB (medial septum/vertical limb of the diagonal band of Broca) resulted in continuous theta field activity regardless of what type of motor behavior the animal performed or whether it was immobile. However, under these conditions the performance of a voluntary movement consistently resulted in an upward shift of theta frequency, demonstrating that the frequency of carbachol-elicited type 2 theta can be modulated by the behavioral activation of type 1 theta. The subsequent infusion of atropine abolished the carbachol-elicited theta, while that occurring during type 1 voluntary movement was preserved. In contrast to the selective blockade of carbachol-elicited theta by atropine, procaine suppression of the MS/vDBB abolished both spontaneous movement-related (type 1) theta and carbachol-elicited (type 2) theta. During the postprocaine period theta frequency recovered rapidly in contrast to theta amplitude (power). This result applied to the recovery of both the coactivated type 1 and type 2 theta occurring during spontaneous movement and the carbachol-elicited type 2 theta alone. The behavioral results were discussed within the context of Bland's (Prog. Neurobiol. 26, 1-54, 1986) sensorimotor model which posits that hippocampal theta activity recorded during voluntary movement represents the coactivation of a cholinergically mediated sensory processing component and a feedback (possibly serotonergic) motor component.

Animals↗

Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.

BACKGROUND: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia. METHODS: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phosphate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly I:C-mice) were examined. RESULTS: In juveniles, no difference was found between the poly I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). Increased dopamine (DA) turnover and decreased receptor binding of D2-like receptors, but not D1-like receptors, in the striatum were found in adult poly I:C-mice. CONCLUSIONS: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.

Animals↗

Model of recovery of locomotor ability after sensorimotor cortex injury in rats.

Animal models of locomotor recovery after brain injury provide tools for understanding the basic neurobiological processes that may underlie recovery after stroke in humans. Measurement of the ability of rats to traverse a narrow elevated beam has proven to be a particularly useful test of locomotor function. Repeated measurement of this behavior over time provides a simple method for quantifying the rate and degree of a rat's locomotor recovery after sensorimotor cortex injury and constitutes a tool for studying its mechanisms and possible treatment strategies. The model has proven particularly useful in predicting the effects of drugs on poststroke recovery in humans.

Animals↗