Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2R binding and reduces striatal D1R binding in male hemiparkinsonian rats

Cerebral administration of botulinum neurotoxin A (BoNT‐A) has been shown to improve disease‐specific motor behavior in a rat model of Parkinson disease (PD). Since the dopaminergic system of the basal ganglia fundamentally contributes to motor function, we investigated the impact of BoNT‐A on striatal dopamine receptor expression using in vitro and in vivo imaging techniques (positron emission tomography and quantitative autoradiography, respectively). Seventeen male Wistar rats were unilaterally lesioned with 6‐hydroxydopamine (6‐OHDA) and assigned to two treatment groups 7 weeks later: 10 rats were treated ipsilaterally with an intrastriatal injection of 1 ng BoNT‐A, while the others received vehicle (n = 7). All animals were tested for asymmetric motor behavior (apomorphine‐induced rotations and forelimb usage) and for striatal expression of dopamine receptors and transporters (D₁R, D₂R, and DAT). The striatal D₂R availability was also quantified longitudinally (1.5, 3, and 5 months after intervention) in 5 animals per treatment group. The 6‐OHDA lesion alone induced a unilateral PD‐like phenotype and a 13% increase of striatal D₂R. BoNT‐A treatment reduced the asymmetry in both apomorphine‐induced rotational behavior and D₂R expression, with the latter returning to normal values 5 months after intervention. D₁R expression was significantly reduced, while DAT concentrations showed no alteration. Independent of the treatment, higher interhemispheric symmetry in raclopride binding to D₂R was generally associated with reduced forelimb akinesia. Our findings indicate that striatal BoNT‐A treatment diminishes motor impairment and induces changes in D₁ and D₂ binding site density in the 6‐OHDA rat model of PD.     

Botulinum toxin type B vs. type A in toxin‐naïve patients with cervical dystonia: Randomized,double‐blind,noninferiority trial

The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT‐A) and type B (BoNT‐B) in toxin‐naïve cervical dystonia (CD) subjects. BoNT‐naïve CD subjects were randomized to BoNT‐A or BoNT‐B and evaluated in a double‐blind trial at baseline and every 4‐weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post‐injection. Secondary measures included change in TWSTRS‐subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT‐B to BoNT‐A. 111 subjects were randomized (55 BoNT‐A; 56 BoNT‐B). Improvement in TWSTRS‐total scores 4 weeks after BoNT‐B was noninferior to BoNT‐A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per‐protocol‐population (PPP)). The median duration of effect of BoNT‐A and BoNT‐B was not different (13.1 vs. 13.7 weeks, respectively; P‐value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT‐B but there were no differences for moderate/severe dry mouth. In this study, both BoNT‐A and B were shown to be effective and safe for the treatment of toxin‐naive CD subjects. © 2007 Movement Disorder Society     

Dopaminergic modulation of motor network compensatory mechanisms in Parkinson's disease

The dopaminergic system has a unique gating function in the initiation and execution of movements. When the interhemispheric imbalance of dopamine inherent to the healthy brain is disrupted, as in Parkinson's disease (PD), compensatory mechanisms act to stave off behavioral changes. It has been proposed that two such compensatory mechanisms may be (a) a decrease in motor lateralization, observed in drug‐naïve PD patients and (b) reduced inhibition ‐ increased facilitation. Seeking to investigate the differential effect of dopamine depletion and subsequent substitution on compensatory mechanisms in non‐drug‐naïve PD, we studied 10 PD patients and 16 healthy controls, with patients undergoing two test sessions — “ON” and “OFF” medication. Using a simple visually‐cued motor response task and fMRI, we investigated cortical motor activation — in terms of laterality, contra‐ and ipsilateral percent BOLD signal change and effective connectivity in the parametric empirical Bayes framework. We found that decreased motor lateralization persists in non‐drug‐naïve PD and is concurrent with decreased contralateral activation in the cortical motor network. Normal lateralization is not reinstated by dopamine substitution. In terms of effective connectivity, disease‐related changes primarily affect ipsilaterally‐lateralized homotopic cortical motor connections, while medication‐related changes affect contralaterally‐lateralized homotopic connections. Our findings suggest that, in non‐drug‐naïve PD, decreased lateralization is no longer an adaptive cortical mechanism, but rather the result of maladaptive changes, related to disease progression and long‐term dopamine replacement. These findings highlight the need for the development of noninvasive therapies, which would promote the adaptive mechanisms of the PD brain.     

Lateralization of brain activity pattern during unilateral movement in Parkinson's disease

We investigated the lateralization of brain activity pattern during performance of unilateral movement in drug‐naïve Parkinson's disease (PD) patients with only right hemiparkinsonian symptoms. Functional MRI was obtained when the subjects performed strictly unilateral right hand movement. A laterality index was calculated to examine the lateralization. Patients had decreased activity in the left putamen and left supplementary motor area, but had increased activity in the right primary motor cortex, right premotor cortex, left postcentral gyrus, and bilateral cerebellum. The laterality index was significantly decreased in PD patients compared with controls (0.41 ± 0.14 vs. 0.84 ± 0.09). The connectivity from the left putamen to cortical motor regions and cerebellum was decreased, while the interactions between the cortical motor regions, cerebellum, and right putamen were increased. Our study demonstrates that in early PD, the lateralization of brain activity during unilateral movement is significantly reduced. The dysfunction of the striatum–cortical circuit, decreased transcallosal inhibition, and compensatory efforts from cortical motor regions, cerebellum, and the less affected striatum are likely reasons contributing to the reduced motor lateralization. The disruption of the lateralized brain activity pattern might be a reason underlying some motor deficits in PD, like mirror movements or impaired bilateral motor coordination. Hum Brain Mapp 36:1878–1891, 2015. © 2015 Wiley Periodicals, Inc .     

Striatal activation by optogenetics induces dyskinesias in the 6‐hydroxydopamine rat model of Parkinson disease

Background : Long‐term levodopa (l ‐dopa) treatment is associated with the development of l ‐dopa–induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l ‐dopa–induced dyskinesias are not well understood. Methods : We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6‐hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno‐associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Results : Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6‐hydroxydopamine lesion but l ‐dopa naïve rats induced involuntary movements similar to l ‐dopa–induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l ‐dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l ‐dopa–induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine‐depleted hemisphere. Conclusion : Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6‐hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato‐nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l ‐dopa–induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society     

MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome

Dysfunction of the ubiquitin‐proteasome system occurs in the substantia nigra (SN) in Parkinson's disease (PD). However, it is unknown whether this is a primary cause or a secondary consequence of other components of the pathogenic process. We have investigated in nonhuman primates whether initiating cell death through mitochondrial complex I inhibition using 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) altered proteasomal activity or the proteasomal components in the SN. Chymotrypsin‐like, trypsin‐like and peptidylglutamyl‐peptide hydrolase (PGPH) activating of 20S proteasome were decreased in SN homogenates of MPTP‐treated marmosets compared to naïve animals. Western blotting revealed a marked decrease in the expression of 20S‐α subunits, but no change in 20S‐β subunits in the SN of MPTP‐treated marmoset compared to naïve animals. There was a marked decrease in the expression of the proteasome activator 700 (PA700) and proteasome activator 28 (PA28) regulatory complexes. The 20S‐α4 subunit immunoreactivity was decreased in the nucleus of colocalized tyrosine hydroxylase (TH)‐positive cells of MPTP‐treated animals compared to naïve animals but no difference in the intensity of 20S‐β1i subunit staining. Immunoreactivity for PA700‐Rpt5 and PA28‐α subunits within surviving TH‐positive cells of MPTP‐treated marmoset was reduced compared to naïve controls. Overall, the changes in proteasomal function and structure occurring follow MPTP‐induced destruction of the SN in common marmosets were very similar to those found in PD. This suggests that altered proteasomal function in PD could be a consequence of other pathogenic processes occurring in SN as opposed to initiating cell death as previously suggested.     

Intrastriatal botulinum toxin abolishes pathologic rotational behaviour and induces axonal varicosities in the 6-OHDA rat model of Parkinson's disease

Central pathophysiological pathways of basal ganglia dysfunction imply a disturbed interaction of dopaminergic and cholinergic circuits. In Parkinson's disease (PD) imbalanced cholinergic hyperactivity prevails in the striatum. Interruption of acetylcholine (ACh) release in the striatum by locally injected botulinum neurotoxin A (BoNT-A) has been studied in the rat 6-hydroxydopamine (6-OHDA) model of PD (hemi-PD). The hemi-PD was induced by injection of 6-OHDA into the right medial forebrain bundle. Motor dysfunction provoked by apomorphine-induced contralateral rotation was completely reversed for more than 3 months by ipsilateral intrastriatal application of 1–2 ng BoNT-A. Interestingly, BoNT-A injected alone into the right striatum of naïve rats caused a slight transient ipsilateral apomorphine-induced rotation, which lasted only for about one month. Immunohistochemically, large axonal swellings appeared within the striatum injected with BoNT-A, which we tentatively named BoNT-A-induced varicosities. They contained either choline acetyltransferase or tyrosine hydroxylase. These findings suggest a selective inhibition of evoked release of ACh by locally applied BoNT-A. Intrastriatal application of BoNT-A may antagonize localized relative functional disinhibited hypercholinergic activity in neurodegenerative diseases such as PD avoiding side effects of systemic anti-cholinergic treatment.     

Combined ipsilateral limb use score as an index of motor deficits and neurorestoration in parkinsonian rats

Our aim was to apply a robust non‐drug induced sensorimotor test battery to assess the efficacy of neurorestorative therapies on the motor deficits caused by partial unilateral 6‐OHDA lesion mimicking early stage PD. Since the 6‐OHDA lesion protocols to induce partial DA depletion in striatum vary extensively between laboratories, we evaluated the associations between different intrastriatal 6‐OHDA doses (1 X 0‐20 and 2 X 0‐30 µg), striatal DA depletion (HPLC‐ECD) and D‐amphetamine induced rotation to identify a lesion protocol that would produce 40‐60% striatal DA depletion. Doses ≥ 6 µg produced a significant DA depletion (ANOVA, P < 0.0001). 6‐OHDA dose range (6‐14 µg) causing 40‐60% DA depletion induced very variable rotational responses. Next, intrastriatal 1 × 10 and 1 × 14 µg doses were compared with a full lesion (10 µg into the medial forebrain bundle) with regard to their effects on adjusting step, cylinder, and vibrissae test performance. A combined ipsilateral score (average of each test) was found more sensitive in distinguishing between different lesions than any test alone. Finally, five‐week treadmill exercise starting two weeks post‐lesion was able to restore impaired limb use (combined score; mixed model, P < 0.05) and striatal DA depletion (ANOVA, P < 0.05) in rats with partial lesion (1 × 10 µg). Notably, D‐amphetamine induced rotation significantly decreased between weeks one to seven post‐lesion (t‐test, P < 0.01). In conclusion, intrastriatal 1 × 10 µg of 6‐OHDA produces 40‐60% striatal DA depletion robustly, and the combined ipsilateral score provides an efficient means for testing of the efficacy of neurorestorative or neuroprotective treatments for PD. © 2017 Wiley Periodicals, Inc.     

Motor‐symptom laterality affects acquisition in Parkinson's disease: A cognitive and functional magnetic resonance imaging study

Background and Objectives : Asymmetric onset of motor symptoms in PD can affect cognitive function. We examined whether motor‐symptom laterality could affect feedback‐based associative learning and explored its underlying neural mechanism by functional magnetic resonance imaging in PD patients. Methods : We recruited 63 early‐stage medication‐naïve PD patients (29 left‐onset medication‐naïve patients, 34 right‐onset medication‐naïve patients) and 38 matched normal controls. Subjects completed an acquired equivalence task (including acquisition, retention, and generalization) and resting‐state functional magnetic resonance imaging scans. Learning accuracy and response time in each phase of the task were recorded for behavioral measures. Regional homogeneity was used to analyze resting‐state functional magnetic resonance imaging data, with regional homogeneity lateralization to evaluate hemispheric functional asymmetry in the striatum. Results : Left‐onset patients made significantly more errors in acquisition (feedback‐based associative learning) than right‐onset patients and normal controls, whereas right‐onset patients performed as well as normal controls. There was no significant difference among these three groups in the accuracy of either retention or generalization phase. The three groups did not show significant differences in response time. In the left‐onset group, there was an inverse relationship between acquisition errors and regional homogeneity in the right dorsal rostral putamen. There were no significant regional homogeneity changes in either the left or the right dorsal rostral putamen in right‐onset patients when compared to controls. Conclusions : Motor‐symptom laterality could affect feedback‐based associative learning in PD, with left‐onset medication‐naïve patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left‐sided onset.© 2016 International Parkinson and Movement Disorder Society     

Induction of GAP‐43 modulates neuroplasticity in PBSC (CD34+) implanted‐Parkinson's model

As a result of the progressive decrease in efficacy of drugs used to treat Parkinson's disease (PD) and the rapid development of motor complications, effective alternative treatments for PD are required. In a 6‐hydroxydopamine (6‐OHDA)‐induced Parkinson's rat model, intracerebral peripheral blood stem cell (CD34⁺) (PBSC) transplantation significantly protected dopaminergic neurons from 6‐OHDA‐induced neurotoxicity, enhanced neural repair of tyrosine hydroxylase neurons through up‐regulation of Bcl‐2, facilitated stem cell plasticity, and attenuated activation of microglia, in comparison with vehicle‐control rats. The 6‐OHDA‐lesioned hemi‐Parkinsonian rats receiving intrastriatal transplantation of PBSCs also showed: 1) enhanced glucose metabolism in the lesioned striatum and thalamus, demonstrated by [¹⁸F]fluoro‐2‐deoxyglucose positron emission tomography (FDG‐PET), 2) improved neurochemical activity as shown by proton magnetic resonance spectroscopy (¹H‐MRS), and 3) significantly reduced rotational behavior in comparison with control lesioned rats. These observations might be explained by an up‐regulation of growth‐associated protein 43 (GAP‐43) expression because improvements in neurological dysfunction were blocked by injection of MK‐801 in the PBSC‐treated group. In addition, a significant increase in neurotrophic factor expression was found in the ipsilateral hemisphere of the PBSC‐treated group. In summary, this protocol may be a useful strategy for the treatment of clinical PD. © 2009 Wiley‐Liss, Inc.     

Effects of kainic acid injections in the striatum on physiologic and behavioral functions in conscious rats

Alterations in both physiologic and behavioral functions were assessed in unanesthetized rats after a unilateral injection of kainic acid (KA) in the striatum. The immediate behavioral effects were dyskinesias, head swaying, circling, tail elevation, hyperpnea and marked salivation. The induced behavioral responses lasted for about 14 to 18 h. Rats with intrastriatal KA injection, although showing no thermoregulatory deficit at both moderate (22 degrees C) and hot (30 degrees C) environmental temperatures, displayed a lower metabolism and a lower rectal temperature than the preinjection controls in the cold (8 degrees C) environment. In addition, the hypothermia induced by intrastriatal administration of apomorphine (dopamine agonist) was greatly antagonized by pretreatment with intrastriatal injection of KA. Furthermore, intrastriatal infusions of KA (1 microgram in 0.5 microliter) also caused a decrease in pain threshold (or in the latency to the hind-paw lick on the hot plate test), hypophagia, polydipsia, and weight loss. The induced alterations in thermoregulation, pain reflex, and ingestive behavior lasted for about 7 days. These data indicate that striatal neurons are involved in the central control of motor activity, thermoregulation, the pain reflex, and ingestive behavior.     

Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats

The vanilloid TRPV1 receptor, present on primary afferent fibres, is activated by noxious heat, low pH and endogenous vanilloids. Changes in the function or distribution of TRPV1 receptors may play an important role in pain induced by inflammation or neuropathy. The aim of the present study was to evaluate the role of peripheral TRPV1 receptors in thermal nociception in rat models of inflammatory and neuropathic pain. Here, we have determined the effects of peripheral administration of the potent TRPV1 receptor antagonist iodoresiniferatoxin (IRTX) on noxious heat (45 °C)‐evoked responses of spinal wide dynamic range (WDR) neurons in naïve, carrageenan‐inflamed, sham‐operated and L5/6 spinal nerve‐ligated (SNL) anaesthetized rats in vivo. In addition, effects of peripheral administration of IRTX on mechanically evoked responses of WDR neurons were determined in sham‐operated and SNL rats. Carrageenan inflammation significantly (P < 0.05) increased the 45 °C‐evoked responses of WDR neurons. Intraplantar injection of the lower dose of IRTX (0.004 µg) inhibited (P < 0.05) 45 °C‐evoked responses of WDR neurons in carrageenan‐inflamed, but not in naïve, rats. The higher dose of IRTX (0.4 µg) significantly (P < 0.05) inhibited 45 °C‐evoked responses in both inflamed and naïve rats. In sham‐operated and SNL rats, IRTX (0.004 and 0.4 µg) significantly (P < 0.05) inhibited 45 °C‐evoked, but had no effect on mechanically evoked responses of WDR neurons. These data support the role of peripheral TRPV1 receptors in noxious thermal transmission in naïve, inflamed and neuropathic rats, and suggest that there is an increased functional contribution of peripheral TRPV1 receptors following acute inflammation.     

Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats

Group A β-hemolytic streptococcal (GAS) infection is associated with a spectrum of neuropsychiatric disorders. The leading hypothesis regarding this association proposes that a GAS infection induces the production of auto-antibodies, which cross-react with neuronal determinants in the brain through the process of molecular mimicry. We have recently shown that exposure of rats to GAS antigen leads to the production of anti-neuronal antibodies concomitant with the development of behavioral alterations. The present study tested the causal role of the antibodies by assessing the behavior of naïve rats following passive transfer of purified antibodies from GAS-exposed rats. Immunoglobulin G (IgG) purified from the sera of GAS-exposed rats was infused directly into the striatum of naïve rats over a 21-day period. Their behavior in the induced-grooming, marble burying, food manipulation and beam walking assays was compared to that of naïve rats infused with IgG purified from adjuvant-exposed rats as well as of naïve rats. The pattern of in vivo antibody deposition in rat brain was evaluated using immunofluorescence and colocalization. Infusion of IgG from GAS-exposed rats to naïve rats led to behavioral and motor alterations partially mimicking those seen in GAS-exposed rats. IgG from GAS-exposed rats reacted with D1 and D2 dopamine receptors and 5HT-2A and 5HT-2C serotonin receptors in vitro. In vivo, IgG deposits in the striatum of infused rats colocalized with specific brain proteins such as dopamine receptors, the serotonin transporter and other neuronal proteins. Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.     

Effects of chronic nicotine administration on nitric oxide synthase expression and activity in rat brain

Although there is substantial evidence concerning the influence of nicotine on nitric oxide (NO) synthesis in the vascular system, there are fewer studies concerning the central nervous system. Although NO metabolites (nitrates/nitrites) increase in several rat brain regions after chronic injection of nicotine, the cellular origin of this rise in NO levels is not known. The aim of the present work was to assess the effects of repetitive nicotine administration on nitric oxide synthase (NOS) expression and activity in male and female rat brains. To determine levels of nitrate/nitrite, the Griess reaction was carried out in tissue micropunched from the frontal cortex, striatum, and accumbens of both male and female rats untreated (naïve) or injected with saline or nicotine (0.4 mg/kg for 15 days). In parallel, coronal sections of fixed brains from equally treated animals were immunostained for neuronal NOS or histochemically labelled for NADPH‐diaphorase activity. Nicotine treatment increased NO metabolites significantly in all brain regions compared with naïve or saline‐treated rats. By contrast, analysis of the planimetric counting of NOS/NADPH‐diaphorase‐positive neurons failed to demonstrate any significant effect of the nicotine treatment. A significant decrease was observed with both techniques employed in saline‐injected female rats compared with naïve animals, suggesting a stress response. The mismatch between the biochemical and the histological data after chronic nicotine treatment is discussed. The up‐regulation of NO sources other than neurons is proposed. © 2002 Wiley‐Liss, Inc.     

The impact of the initial severity on later outcome: retrospective analysis of a large cohort of botulinum toxin naïve patients with idiopathic cervical dystonia

Journal of Neurology - The aim of study was to demonstrate that the first three injections of botulinum neurotoxin type A (BoNT/A) appear to be less effective in botulinum toxin naïve patients...     

Evaluation of simple and complex sensorimotor behaviours in rats with a partial lesion of the dopaminergic nigrostriatal system

We have examined the behavioural consequences of a partial unilateral dopaminergic denervation of the rat striatum. This partial lesion was obtained by an intrastriatal 6-hydroxy-dopamine injection (6-OHDA, 20 or 10 microgram divided between two injection sites) and was compared with a unilateral complete lesion resulting from an injection of 6-OHDA (2 x 6 microgram) into the medial forebrain bundle. Quantification of striatal dopamine (DA) and its metabolites, and the immunohistochemical evaluation of the nigrostriatal DA system confirmed the complete and partial lesions. Animals with complete striatal denervation displayed both apomorphine- and amphetamine-induced rotations whereas the partial denervation elicited amphetamine-induced rotations only. However, the rates of amphetamine-induced rotation were not correlated with the size of the lesion. In contrast, the paw-reaching impairments were significantly correlated with the striatal dopaminergic depletion. When evaluated in the staircase test, animals with partial denervation were impaired exclusively for the paw contralateral to the side of the lesion. This motor deficit (50-75%) included all components of the skilled paw use (i.e. attempt, motor coordination and success) and was observed at least 12 weeks after the lesion. However, these animals were able to perform normal stepping adjustments with the impaired paw, indicating that the partial lesion induced a coordination deficit of the paw rather than a deficit of movement initiation. After a complete lesion, stepping adjustments of the contralateral paw were dramatically impaired (by 80%), an akinesia which almost certainly accounted for the great deficit in skilled paw use. The paw-reaching impairments resulting from the partial striatal denervation are proposed as a model of the early symptoms of Parkinson's disease and may be useful for the development of restorative therapies.     

Immediate early gene activity‐regulated cytoskeletal‐associated protein regulates estradiol‐induced lordosis behavior in female rats

Sensory feedback is an important component of any behavior, with each instance influencing subsequent activity. Female sexual receptivity is mediated both by the steroid hormone milieu and interaction with the male. We tested the influence of repeated mating on the level of sexual receptivity in ovariectomized rats treated with estradiol benzoate (EB) once every fourth day to mimic the normal phasic changes of circulating estradiol. Females were divided into two groups: naïve, which were tested for lordosis behavior once, and experienced rats, which were tested for lordosis after each EB injection. To monitor the effect of mating, the number of neurons expressing the immediate early gene activity‐regulated cytoskeleton‐associated protein (Arc) were counted in the mediobasal hypothalamus. Females were unreceptive following the first EB treatment, but the mating induced Arc expression. In naïve rats, each subsequent EB injection increased the levels of sexual receptivity. This ramping was not observed in experienced rats, which achieved only a moderate level of sexual receptivity. However, experienced females treated with EB and progesterone were maximally receptive and did not have Arc expression. To test whether the expression of Arc attenuated lordosis, Arc antisense oligodeoxynucleotides (asODN) were microinjected into experienced females' arcuate nuclei. Arc expression was attenuated, and the experienced EB‐treated females achieved maximal sexual receptivity. These results demonstrate that Arc expression in the hypothalamus might influence future sexual receptivity and provides evidence of learning in the arcuate nucleus. The loss of Arc results in unrestrained sexual receptivity. © 2014 Wiley Periodicals, Inc.     

Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants

Intrastriatal transplantation of fetal ventral mesencephalon (VM) is currently explored as a potential clinical therapy in Parkinson's disease (PD). Although providing substantial benefit for the patient, behavioral recovery so far obtained with intrastriatal VM grafts is not complete. Using the 6-hydroxydopamine lesion model of PD, we show here that near-complete restoration of the striatal dopamine (DA) innervation can be achieved by multiple intrastriatal microtransplants of fetal DA cells; nevertheless, complete recovery in complex sensorimotor behaviors was not obtained in these animals. In line with the current model of basal ganglia function, this suggests that the lesion-induced overactivity of the basal ganglia output structures, i.e., the substantia nigra (SN) and the entopeduncular nucleus, may not be completely reversed by intrastriatal VM grafts. In the present study, we have transplanted fetal VM tissue or fetal striatal tissue, as a source of DA and GABA neurons, respectively, into the SN of DA-depleted rats. Intranigral VM grafts induced behavioral recovery in some sensorimotor behaviors (forelimb akinesia and balance tests), but the effect did not exceed the recovery observed after intrastriatal VM grafts. Intranigral grafts of striatal tissue induced a pattern of functional recovery which was distinctly different from that observed after intranigral VM grafts, and recovery in coordinated forelimb use in the paw-reaching test was even more pronounced than after intrastriatal transplantation of VM cells. Combined transplantation of DA neurons into the striatum and GABA-rich striatal neurons into the SN induced additive effects of behavioral recovery observed in the forelimb akinesia test. We propose that intranigral striatal transplants, by a GABA-mediated inhibitory action, can reduce the overactivity of the host SN projection neurons and can induce significant recovery in complex motor behavior in the rat PD model and that such grafts may be used to increase the overall functional efficacy of intrastriatal VM grafts.