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Amputation with Median Nerve Redirection (Targeted Reinnervation) Reactivates Forepaw Barrel Subfield in Rats

Paul D. Marasco, Todd A. Kuiken

The Journal of Neuroscience

, November 2010

Prosthetic limbs are difficult to control and do not provide sensory feedback. Targeted reinnervation was developed as a neural–machine interface for amputees to address these issues. In targeted reinnervation, amputated nerves are redirected to proximal muscles and skin, creating nerve interfaces for prosthesis control and sensory feedback. Touching the reinnervated skin causes sensation to be projected to the missing limb. Here we use electrophysiological brain recording in the Sprague Dawley rat to investigate the changes to somatosensory cortex (S1) following amputation and nerve redirection with the intent to provide insight into the sensory phenomena observed in human targeted reinnervation amputees. Recordings revealed that redirected nerves established an expanded representation in S1, which may help to explain the projected sensations that encompass large areas of the hand in targeted reinnervation amputees. These results also provide evidence that the reinnervated target skin could serve as a line of communication from a prosthesis to cortical hand processing regions. S1 border regions were simultaneously responsive to reinnervated input and also vibrissae, lower lip, and hindfoot, suggesting competition for deactivated cortical territory. Electrically evoked potential latencies from reinnervated skin to cortex suggest direct connection of the redirected afferents to the forepaw processing region of S1. Latencies also provide evidence that the widespread reactivation of S1 cortex may arise from central anatomical interconnectivity. Targeted reinnervation offers the opportunity to examine the cortical plasticity effects when behaviorally important sensory afferents are redirected from their original location to a new skin surface on a different part of the body.

Characterization of Some Morphological Parameters of Orbicularis Oculi Motor Neurons in the Monkey

D. W. Mcneal, J. Ge, J. L. Herrick, K. S. Stilwell-morecraft, R. J. Morecraft

Neuroscience 151

, 12–27

, 2008

Key words: blinking, facial expression, cranial nerves, pons, non-human primate

The primate facial nucleus is a prominent brain- stem structure that is composed of cell bodies giving rise to axons forming the facial nerve. It is musculotopically orga- nized, but we know little about the morphological features of its motor neurons. Using the Lucifer Yellow intracellular fill- ing method, we examined 11 morphological parameters of motor neurons innervating the monkey orbicularis oculi (OO) muscle, which plays an important role in eyelid closure and voluntary and emotional facial expressions. All somata were multipolar and remained confined to the intermediate subnu- cleus, as did the majority of its aspiny dendritic branches. We found a mean maximal cell diameter of 54 μm in the trans- verse dimension, cell diameter of 60 μm in the rostrocaudal dimension, somal surface area of 17,500 μm2 and somal volume of 55,643 μm3. Eight neurons were used in the anal- ysis of dendritic parameters based upon complete filling of the distal segments of the dendritic tree. We found a mean number of 16 dendritic segments, an average dendritic length of 1036 μm, diameter of 7 μm, surface area of 12,757 μm2 and total volume of 16,923 μm3. Quantitative analysis of the den- dritic branch segments demonstrated that the average num- ber, diameter and volume gradually diminished from proxi- mal to distal segments. A Sholl analysis revealed that the highest number of dendritic intersections occurred 60 μm distal to the somal center with a gradual reduction of inter- sections occurring distally. These observations advance our understanding of the morphological organization of the pri- mate facial nucleus and provide structural features for com- parative studies, interpreting afferent influence on OO func- tion and for designing studies pinpointing structural alter- ations in OO motor neurons that may accompany disorders affecting facial movement. Published by Elsevier Ltd on be- half of IBRO.

Biodistribution of Adeno-associated Virus Type-2 in Nonhuman Primates after Convection-enhanced Delivery to Brain

Janet Cunningham, Philip Pivirotto, John Bringas, Brian Suzuki, Sharmila Vijay, Laura Sanftner, Marina Kitamura, Curtis Chan, Krystof S Bankiewicz

Molecular Therapy

, 16 7, 1267–1275 doi:10.1038/mt.2008.111

, June 3, 2008

A combination treatment of AAV2-hAADC with oral levodopa is a novel therapeutic approach that is being developed for late-stage Parkinson’s disease. Biodistribution of AAV2-hAADC was assessed over a wide range of vector dose in 12 monkeys with parkinsonian syndrome, 6 months after intraputamenal infusion. Quantitative PCR (Q-PCR) from all the major neuroanatomical regions of the brain indicated a dose-dependent increase in vector DNA, with 99% being detected in the target site and other basal ganglia tissues. Within these tissues, the distribution varied widely between the putamen (PT) and the globus pallidus, and this was attributed to differences in vector transport. Q-PCR and immunocytochemistry were consistent with results reported earlier for various measures of transgene expression including aromatic l-amino acid decarboxylase (AADC) activity assays, behavioral response, and in vivo imaging with positron emission tomography (PET). Outside of the brain, trace amounts of vector DNA were detected in the spleens of animals in the two highest dose groups, but not in any other peripheral tissue, blood, or cerebrospinal fluid. Some increase in neutralizing antibody titers to adeno-associated virus type-2 (AAV2) capsid protein was observed in monkeys that received high doses of AAV2-hAADC or control AAV2-GFP. This study further validates convection-enhanced delivery (CED) as the preferred method of viral vector delivery to the brain, and supports a Phase I clinical testing of AAV2-hAADC in humans with Parkinson’s disease.

Comparing the Melanin-concentrating Hormone -1 Receptor Expression in the Brains of Mice and Rats

Sidney Clayborn Williams III

The University Of Texas at Arlington

, May 2007

The melanin-concentrating hormone (MCH) family of neuropeptides is believedto be important in controlling certain feeding behaviors. This family consists of one ligand, melanin-concentrating hormone (MCH), and two receptors, melanin- concentrating-1 receptor (MCH-1R) and melanin-concentrating-2 receptor (MCH-2R), of which only MCH-1R is expressed in rodents. Recently, the distribution of MCH-1R in rat brains was published revealing that it is expressed throughout the rat brain in a complex and widespread manner. Moreover, mice lacking MCH and MCH-1R have been generated and have been found to be leaner and more active than their wild-type littermates. Consequently, MCH-1R has become a possible site for pharmacologicalinteraction to control obesity. Many of these experiments are being performed utilizing ivmice however, the areas expressing MCH-1R in the mouse brain still remain unknown. Therefore, in situ hybridization was performed in both mouse and rat brain samples to elucidate the MCH-1R mRNA expression in the mouse and to compare these results with the expression in the rat. This comparison study revealed that most of the positive nuclei evaluated were represented in both rodent models and that these areas displayed similar expression intensities. However, a subset of nuclei was found to display a different MCH-1R expression between these two rodent species. These expression differences reside in brain areas important in reward, motivation, movement, visualization, vigilance, and learning, and could possibly explain differences in feeding and foraging behaviors between mice and rats.

Distribution of norepinephrine transporters in the non-human primate brain

H.R. Smith, T.J.R. Beveridge, L.J. Porrino

The Journal of Neuroscience

, Vol 138, Issue 2

, 2006

Key words: norepinephrine transporter; [3H]nisoxetine; rhesus monkey; autoradiography

Noradrenergic terminals in the central nervous system are widespread; as such this system plays a role in varying functions such as stress responses, sympathetic regulation, attention, and memory processing, and its dysregulation has been linked to several pathologies. In particular, the norepinephrine transporter is a target in the brain of many therapeutic and abused drugs. We used the selective ligand [³H]nisoxetine, therefore, to describe autoradiographically the normal regional distribution of the norepinephrine transporter in the non-human primate central nervous system, thereby providing a baseline to which alterations due to pathological conditions can be compared. The norepinephrine transporter in the monkey brain was distributed heterogeneously, with highest levels occurring in the locus coeruleus complex and raphe nuclei, and moderate binding density in the hypothalamus, midline thalamic nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala, and brainstem nuclei such as the dorsal motor nucleus of the vagus and nucleus of the solitary tract. Low levels of binding to the norepinephrine transporter were measured in basolateral amygdala and cortical, hippocampal, and striatal regions. The distribution of the norepinephrine transporter in the non-human primate brain was comparable overall to that described in other species, however disparities exist between the rodent and the monkey in brain regions that play a role in such critical processes as memory and learning. The differences in such areas point to the possibility of important functional differences in noradrenergic information processing across species, and suggest the use of caution in applying findings made in the rodent to the human condition.

Rotenone induces non-specific central nervous system and systemic toxicity

Nicolas Lapointe, Michel St-Hilaire, Maria-Grazia Martinoli, Julie Blanchet, Peter Gould, Claude Rouillard, and Francesca Cicchetti

The FASEB Journal

, 10.1096/fj.03-0677fje

, 2004

Key words: Parkinson’s disease, basal ganglia, pesticide, neurotoxicity, inflammation

We investigated the dopaminergic (DA) neuronal degeneration in animals subjected to systemic treatment of rotenone via subcutaneous delivery. Behavioral observations revealed a hypokinetic period in rats sacrificed at 3 and 5 days, and dystonic episodes in animals sacrificed at 8 days. Less than 20% of the total number of animals given rotenone depicted brain lesions after 8 days of treatment, as demonstrated by a significant loss of DA fibers in the striatum, but not of DA nigral neurons. Tyrosine hydroxylase-negative striatal territories were characterized by post- synaptic toxicity as demonstrated by a decreased number of interneurons labeled for choline acetyltransferase, NADPH-diaphorase, parvalbumin, and projection neurons labeled for calbindin and nerve growth factor inducible-B (NGFI-B). Post-synaptic neurodegeneration was demonstrated further by abundant striatal staining for Fluoro-Jade. Decrease in the nuclear orphan receptor Nurr1 expression was the only significant change observed at the level of the substantia nigra. Autopsy reports confirmed that animals suffered from severe digestion problems. These data suggest that hypokinesia observed between 3 and 5 days is the result of general health problems rather than a specific motor deficit associated to Parkinson’s disease (PD) symptoms. Overall, the effects of rotenone toxicity are widespread, and subcutaneous administration of this toxin does not provide the neuropathological and behavioral basis for a relevant and reliable PD model.