Cholinergic upregulation by optogenetic stimulation of nucleus basalis after photothrombotic stroke in forelimb somatosensory cortex improves endpoint and motor but not sensory control of skilled reaching in mice.

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.

Skilled movement and posture deficits in rat string-pulling behavior following low dose space radiation (28Si) exposure.

Deep space flight missions beyond the Van Allen belt have the potential to expose astronauts to space radiation which may damage the central nervous system and impair function. The proposed mission to Mars will be the longest mission-to-date and identifying mission critical tasks that are sensitive to space radiation is important for developing and evaluating the efficacy of counter measures. Fine motor control has been assessed in humans, rats, and many other species using string-pulling behavior. For example, focal cortical damage has been previously shown to disrupt the topographic (i.e., path circuity) and kinematic (i.e., moment-to-moment speed) organization of rat string-pulling behavior count to compromise task accuracy. In the current study, rats were exposed to a ground-based model of simulated space radiation (5 cGy 28Silicon), and string-pulling behavior was used to assess fine motor control. Irradiated rats initially took longer to pull an unweighted string into a cage, exhibited impaired accuracy in grasping the string, and displayed postural deficits. Once rats were switched to a weighted string, some deficits lessened but postural instability remained. These results demonstrate that a single exposure to a low dose of space radiation disrupts skilled hand movements and posture, suggestive of neural impairment. This work establishes a foundation for future studies to investigate the neural structures and circuits involved in fine motor control and to examine the effectiveness of counter measures to attenuate the effects of space radiation on fine motor control.

Organization of the reach and grasp in head-fixed vs freely-moving mice provides support for multiple motor channel theory of neocortical organization.

Multiple motor channel (MMC) theory of neocortical organization proposes that complex movements, such as reaching for a food item to eat, are produced by the coordinated action of separate neural channels. For example, the human reach-to-grasp act is mediated by two visuo-parieto-motor cortex channels, one for the reach and one for the grasp. The present analysis asked whether there is a similar organization of reach-and-grasp movements in the mouse. The reach-to-eat movements of the same mice were examined from high-shutter speed, frame-by-frame video analysis in three tasks in which the mice obtained equivalent success scores: when freely-moving reaching for food pellets, when head-fixed reaching for food pellets, and when head-fixed reaching for pieces of pasta. To reach, the mice used egocentric cues to vary upper arm movements in a task-appropriate manner to place an open hand on the food or to locate the food using a "touch-release-grasp" strategy. Although mice could not hand-shape offline when reaching, they could hand-shape using online touch-related cues from the mouth to manipulate the food at the mouth. That the reach can be performed offline in relation to egocentric cues whereas hand shaping for the grasp requires online cues supports the idea that for the mouse, as for primates, the reach and grasp are separate acts. The results are further discussed in relation to the use of the head-fixed behavioral procedure to identify the independent neural substrates of the reach and the grasp using mesoscale stimulation/imaging methods.

Dissociation of the Reach and the Grasp in the destriate (V1) monkey Helen: a new anatomy for the dual visuomotor channel theory of reaching.

Dual visuomotor channel theory proposes that reaching depends on two neural pathways that extend from visual cortex (V1) to motor cortex via the parietal lobe. The Reach pathway directs the hand to the target's location and the Grasp pathway shapes the hand and digits for purchase. Sighted human participants integrate the Reach and the Grasp, but without vision they dissociate the movements to capitalize on tactile cues. They use a Reach with a relatively open hand to locate the target and then they use touch cues to shape the fingers to Grasp. After a V1 lesion, the rhesus monkey, Helen, learned to make near-normal visual discriminations based on size and brightness but displayed visual agnosia. She also learned to reach for food with her mouth and her hands. The present analysis of film of her reaching behavior shows that she dissociated the Reach and the Grasp, as do unsighted human participants reaching for a food target at a fixed location. Her rapid and direct Reach was made with an open hand and extended fingers to contact the food with the palm whereas her Grasp was initiated after she touched the food. She also visually fixated the target during the Reach and visually disengaged after target contact, as do sighted human participants. In contrast, Helen did integrate the Reach and the Grasp to take food from her mouth, demonstrating that she could integrate the movements using online tactile cues. The finding that extrastriate pathways can direct the hand toward extrinsic target properties (location) but not intrinsic target properties (size and shape) is discussed as a novel addition to dual visuomotor channel theory.

Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception.

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.

Reaching-to-eat in humans post-stroke: fluctuating components within a constant pattern.

Reaching movements of the arm and hand become automatic early in development and are used throughout one's life span. Studies on skilled reaching have focused on the kinematic aspects and have advanced our knowledge of the individual motor components of reaching. It has also been shown that motor behaviors are organized in terms of ethologically relevant actions, rather than by motor components. Thus, it is important to analyze how the motor components of reaching are performed within the overall action as a whole. The objective of the present study was to examine the motor components of reaching-to-eat within the context of the overall behavior in stroke participants. Results show that reaching-to-eat involves the whole body to produce isolated actions of the limb and changes after stroke in three fundamental ways: abnormal use of nonkinematic aspects of movement, body-limb disintegration, and a disruption in the temporal aspect of the phases of reaching-to-eat. The movements within the behavior can reorganize, possibly a reflection of dynamic interactions between behavioral compensation and neuroplasticity, while the overall performance of the behavior remains the same. Such subtle flexibility may be part of the process of recovery.

Individual differences in skilled reaching for food related to increased number of gestures: evidence for goal and habit learning of skilled reaching.

Skilled reaching in rodents and primate is motorically similar, but success in reaching by rodents is distinctively variable. The source of this variability has not been examined previously. Long-Evans rats were videotaped as they reached for food in 2 different reaching tasks, and endpoint measures of performance were examined in relation to variables previously associated with individual differences, including testing procedures, rehabilitation, movement ability, general locomotor activity, and cortical anatomy. There were individual differences in performance, but these were not related to the dependent measures related to training, movement ability, locomotor activity, or anatomy (e.g., brain with cortical thickness, acetylcholinesterase and neuron density, pyramidal tract size). Success was negatively related to numbers of gestures (non-weight-bearing movements of the reaching limb) used on a reach, however. The results are discussed in relation to the idea that individual differences in response strategy bias some rats to use a more successful goal strategy and others to use a less successful habit strategy for skilled reaching.

Nicotine does not improve recovery from learned nonuse nor enhance constraint-induced therapy after motor cortex stroke in the rat.

Nicotine, a cholinergic agonist, rapidly crosses the blood-brain barrier, promotes neuronal plasticity and has been suggested to enhance behavior in a variety of neurological conditions. Nicotine has also been suggested to benefit functional recovery in rodent models of stroke. At present there has been no systematic investigation of the potential benefits of nicotine therapy in both the acute and chronic post-stroke period. This was the objective of the present study and to that end, the effects of nicotine administration prior to and following motor cortex stroke were examined in a skilled reaching task. The task provides a thorough assessment of learned nonuse and constraint-induced recovery of behavior as determined by both end-point and movement element analysis. Nicotine (0.3 mg/kg p.o.) was administered twice daily during reach training and following motor cortex stroke. Rats were divided into four groups based on their pre-/post-stroke treatment: nicotine/nicotine, nicotine/vehicle, vehicle/nicotine, vehicle/vehicle. After stroke, nicotine did not counteract learned nonuse, facilitate constraint-induced therapy, or improve long-term recovery as measured by end-point analysis and movement element analysis. The results are discussed in relation to the problem of identifying pharmacotherapeutic agents that augment rehabilitation following stroke.

Use of rotorod as a method for the qualitative analysis of walking in rat.

High speed video analysis of the details of movement can provide a source of information about qualitative aspects of walking movements. When walking on a rotorod, animals remain in approximately the same place making repetitive movements of stepping. Thus the task provides a rich source of information on the details of foot stepping movements. Subjects were hemi-Parkinson analogue rats, produced by injection of 6-hydroxydopamine (6-OHDA) into the right nigrostriatal bundle to deplete nigrostriatal dopamine (DA). The present report provides a video analysis illustration of animals previously were filmed from frontal, lateral, and posterior views as they walked (15). Rating scales and frame-by-frame replay of the video records of stepping behavior indicated that the hemi-Parkinson rats were chronically impaired in posture and limb use contralateral to the DA-depletion. The contralateral limbs participated less in initiating and sustaining propulsion than the ipsilateral limbs.These deficits secondary to unilateral DA-depletion show that the rotorod provides a use task for the analysis of stepping movements.A more detailed presentation of the present study has been made (Whishaw et al, 2003), but the present study presents the video support describing the stepping movement in the good and affected limbs of unilateral dopamine-depleted rats. For the analysis, rats with unilateral DA depletions and control rats were video recorded from front, lateral and posterior views. A rating scale of posture and forelimb movements indicated that stepping movements were chronically impaired following surgery. Examination of limb movements indicated that whereas the DA-depleted rats could use the limbs contralateral to the lesion for support, they received minimal use for shifting weight. The results of this study indicate that the rotorod task, in addition to providing quantitative measures of motor impairments, can also provide insights into the qualitative impairments [corrected].

Play fighting in androgen-insensitive tfm rats: evidence that androgen receptors are necessary for the development of adult playful attack and defense.

The frequency of playful attack and the style of playful defense, are modifiable by gonadal steroids and change after puberty in male and female rats. The present study examined the play behavior exhibited by testicular feminized mutation (tfm)-affected males, who are insensitive to androgens but can bind estrogens aromatized from androgens, to determine the relative contributions of androgens and estrogens to the age-related changes in play behavior. tfm males did not exhibit a decrease in playful attack with age and were more likely to maintain the use of complete rotations, a juvenile form of playful defense, into adulthood. tfm males did however, show age related changes in the use of partial rotations and upright postures, two other forms of playful defense, that were similar to normal males. These data suggest that the development of play fighting and defense in males is dependent on both androgen- and estrogen-receptor-mediated effects.

Pallidal deep brain stimulation and L-dopa do not improve qualitative aspects of skilled reaching in Parkinson's disease.

OBJECTIVE: To determine effects of dopaminergic medication and pallidal deep brain stimulation (DBS) on skilled reach in Parkinson's disease (PD). BACKGROUND: PD is a neurodegenerative disorder affecting motor control. While speed and execution of movements are improved by L-dopa, not all motor symptoms are alleviated. Little is known about the effects of DBS or medication on reaching. DESIGN METHOD: Eight PD patients with unilateral pallidal DBS reached with the contra-lateral hand for a piece of food, placing it in the mouth, and returning to starting position. Testing was performed on no treatment, medication only, DBS only, and combined treatment. Reaches were digitally recorded and analyzed on a 21 point scale adapted from Eshkol-Wachman Notation. Analysis was blinded, with patients compared to age-matched controls. RESULTS: Patients were tested 6-13 months after surgery. All showed significant improvement clinically and in UPDRS (III) scores. The following data were obtained on the reaching scale: normal controls 16.5-21.0 (mean 18.3), no treatment 3.0-12.5 (mean 7.4), medication only 7.0-14.0 (mean 10.3), DBS only 4.5-16.0 (mean 9.2), combined treatment 4.0-15.0 (mean 9.5). The difference between controls and all treatment groups was statistically significant (P<0.005). All aspects of reach were compromised. No significant differences were found among the four conditions. CONCLUSIONS: This study is consistent with accumulating evidence that some aspects of motor performance in PD patients, such as reaching, are resistant to L-dopa. Also, pallidal DBS does not improve those parameters that are resistant to L-dopa, either alone or in combination with medication.

Nicotine stimulates dendritic arborization in motor cortex and improves concurrent motor skill but impairs subsequent motor learning.

The effect of the premature commitment of neurons to exuberant growth by nicotine on concurrent and subsequent learning is unknown and was the focus of the present study. Animals were trained on a tray reaching for food task (where lots of pieces of chicken feed were available) for 3 weeks before they received two daily injections of nicotine (0.3 mg/kg) or 0.9% saline for 12 days. Measures of tray-reaching performance were obtained before the administration of nicotine and every other week for a total of 7 weeks. Starting on week 8, animals were given a novel motor skill problem that required them to learn to use a forepaw to reach through a slot in a cage for single food pellets located on an external shelf. Pyramidal cells in the forelimb area of both hemispheres were then examined for dendritic length and branching using a Golgi-Cox procedure. Animals treated with saline displayed excellent performance in both reaching tasks and an increase in neuronal branching in Layer V pyramidal cells in the motor cortex contralateral to the reaching paw. In contrast, animals treated with nicotine showed bilateral increases in neuronal branching. Behavioral results showed that nicotine improved forelimb use in the concurrently administered tray-reaching task, but severely degraded quantitative and qualitative scores of skilled forelimb use in the subsequently administered single-pellet reaching task. The results suggest that plasticity coincidence with skilled training is essential to skilled motor learning, but this expenditure can impair subsequent learning.

A masculinized skeletomusculature is not necessary for male-typical patterns of food-protective movement.

Although sexual dimorphism in movement has been documented in rodents, the extent to which it relates to dimorphic neural control versus dimorphic body size/structure is unclear. We have shown previously that male and female rats are sexually dimorphic with regards to the lateral movements and hindpaw stepping they use to protect a food item. We addressed the question of whether this sexual dimorphism is due to sex differences in peripheral skeletomusculature or in the CNS by examining the movement composition used during dodging to protect a food item by tfm-affected males and their wild-type male (WTM) and female (WTF) controls. The tfm-affected male, while genetically male, develops internal testes that secrete testosterone, but is phenotypically female due to a failure of androgen receptor-mediated masculinization of the periphery. Masculinization of the CNS of tfm-affected males, however, is primarily accomplished by the actions of testosterone's aromatized metabolite estradiol acting via estrogen receptors. Thus the tfm-affected male provides an assay by which the relative contributions of the skeletomusculature or CNS to sex differences in movement organization can be addressed. We found that female wild-type animals were significantly different from both the tfm-affected and wild-type males. There were no significant differences in dodge patterns used by tfm-affected males and their wild-type male controls. This study provides evidence that the sex differences in dodging patterns are mediated primarily by CNS mechanisms and are not primarily dependent on a male- or female-typical skeletomusculature.

Distinct forelimb and hind limb stepping impairments in unilateral dopamine-depleted rats: use of the rotorod as a method for the qualitative analysis of skilled walking.

The rotorod test, in which animals walk on a rotating drum, is widely used to assess motor status in laboratory rodents. Performance is measured by the duration that an animal stays up on the drum as a function of drum speed. Here we report that the task provides a rich source of information about qualitative aspects of walking movements. Because movements are performed in a fixed location, they can readily be examined using high-speed video recording methods. The present study was undertaken to examine the potential of the rotorod to reveal qualitative changes in the walking movements of hemi-Parkinson analogue rats, produced by injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal bundle to deplete nigrostriatal dopamine (DA). Beginning on the day following surgery and then periodically over the next two months, the rats were filmed from frontal, lateral, and posterior views as they walked on the rotorod. Behavior was analyzed by frame-by-frame replay of the video records. Rating scales of stepping behavior indicated that the hemi-Parkinson rats were chronically impaired in their posture and in the use of the limbs contralateral to the DA-depletion. The contralateral limbs not only displayed postural and movement abnormalities, they participated less in initiating and sustaining propulsion than did the ipsilateral limbs. These findings not only reveal new deficits secondary to unilateral DA-depletion, but also show that the rotorod can provide a robust tool for the qualitative analysis of movement.

Impaired dodging in food-conflict following fimbria-fornix transection in rats: a novel hippocampal formation deficit.

It is well known that damage to the hippocampal formation (Ammon's horn, dentate gyrus, fimbria-fornix, and other pathways) produces impairments in spatial navigation and in certain forms of learning. Lesions within these structures have also been reported to produce some motor impairments, but the nature of these impairments is less understood. The present study examined the effects of fimbria-fornix lesions on food wrenching and dodging, social interactions that occur when one rat attempts to steal food from a conspecific, who in turn attempts to protect the food by an evasive movement. Lesion effectiveness was confirmed histologically and electrophysiologically, by the loss of hippocampal rhythmical slow-wave activity (RSA or theta), and by changes in open field behavior (increased open field behavior, less thigmotaxis and more defecation). Analysis of the social interaction indicated when an eating control rat was approached by a conspecific that was attempting to steal its food, it prevented the theft by dodging, a rapid lateral maneuver involving forequarter turning and stepping with the rear limbs. Rats with fimbria-fornix lesions were significantly impaired in dodging and so were more likely to lose their food to the robber. This novel deficit in motor behavior is discussed in relation to contemporary theories of hippocampal function and it is suggested that the deficit may be caused by an inability of the fimbria-fornix damaged animals to disengage attention from eating in order to initiate an evasive movement to protect food. The finding of this novel deficit underscores the importance of considering both loss as well as release phenomena in the analysis of hippocampal formation function.

Quantification of a single exploratory trip reveals hippocampal formation mediated dead reckoning.

A rat's proclivity to explore a novel environment presents a behaviorally rich paradigm to investigate the role of the hippocampus in spatial navigation. Here we describe a novel technique of behavioral analysis that is derived from a single exploratory trip. An exploratory trip was defined as a rat's departure from the home base that ended when the rat returned to the home base. The behavior observed on a single exploratory trip by a control animal is highly organized into outward and homeward segments. An outward segment is characterized by a slow circuitous progression from the home base marked by several stops. A homeward segment is characterized by a rapid direct return to the home base. The velocity attribute of the exploratory trip was quantified by estimating the point of inflection associated with the trip's cumulative moment-to-moment velocity distribution. The heading direction and variance of the homeward trip segment was analyzed with circular statistics. A comparison of the exploratory behavior of control animals and animals with damage to the fimbria-fornix indicated that the velocity and heading direction of the homeward portion of the trip depends upon the hippocampal formation. While control and fimbria-fornix rats had similar outward segments, the return paths of the fimbria-fornix rats were significantly slower, more circuitous, and more variable compared with that of the control rats. This result was also independent of testing in light or dark conditions. The lack of dependence on allothetic cues suggests that rats employ dead reckoning navigational strategies to initiate the homeward portion of exploratory movements. Methods to quantify exploratory behavior in terms of velocity and angular components provide an assessment of control behavior and the assessment of the behavior of rats with hippocampal formation damage that is easy to implement.

DREAM is a critical transcriptional repressor for pain modulation.

Control and treatment of chronic pain remain major clinical challenges. Progress may be facilitated by a greater understanding of the mechanisms underlying pain processing. Here we show that the calcium-sensing protein DREAM is a transcriptional repressor involved in modulating pain. dream(-/-) mice displayed markedly reduced responses in models of acute thermal, mechanical, and visceral pain. dream(-/-) mice also exhibited reduced pain behaviors in models of chronic neuropathic and inflammatory pain. However, dream(-/-) mice showed no major defects in motor function or learning and memory. Mice lacking DREAM had elevated levels of prodynorphin mRNA and dynorphin A peptides in the spinal cord, and the reduction of pain behaviors in dream(-/-) mice was mediated through dynorphin-selective kappa (kappa)-opiate receptors. Thus, DREAM appears to be a critical transcriptional repressor in pain processing.