The neuropharmacological profile of interval responding during operant tasks.

Responses occurring during intervals of operant tasks have been subdivided as interim, facultative, and terminal, depending on the time between response onset and reward. Although interval responses, also known as adjunctive responses, have been described in pigeons, rats, mice, monkeys, and humans, most experiments have been conducted in rats. We review the neurochemical basis of interval responses and examine the hypothesis that these responses modulate operant performance. Preliminary experiments indicate the involvement of biogenic amines, acetylcholine, and GABA during interval responding associated with operant tasks. In particular, catecholaminergic deafferentation of the basal ganglia modulated interval responses as did the peripheral injection of catecholamine reuptake blockers. Under the influence of amphetamine, interval responding may either increase or decrease, so that a wide range of responses must be selected to gauge drug effects. In non-drugged pigeons and rats, the expression of interval responses facilitates operant training.

The Neuroanatomical Basis of the 5-HT Syndrome and Harmalineinduced Tremor.

The 5-HT syndrome in rats is composed of head weaving, body shaking, forepaw treading, flat body posture, hindlimb abduction, and Straub tail. The importance of the brainstem and spinal cord for the syndrome is underlined by findings of 5,7-dihydroxytryptamine (5,7-DHT)-induced denervation supersensitivity in response to 5-HT-stimulant drugs. For head weaving and Straub tail, supersensitivity occurred when the neurotoxin was injected into the cisterna magna or spinal cord, for forepaw treading in cisterna magna, and for hindlimb abduction in the spinal cord. Although 5,7- DHT-related body shaking increased in the spinal cord, the sign decreased when injected into the striatum, indicating the modulatory influence of the basal ganglia. Further details on body shaking are provided by its reduced response to harmaline after 5-HT depletion caused by intraventricular 5,7-DHT, electrolytic lesions of the medial or dorsal raphe, and lesions of the inferior olive caused by systemic injection of 3-acetylpyridine along with those found in Agtpbp1pcd or nr cerebellar mouse mutants. Yet the influence of the climbing fiber pathway on other signs of the 5-HT syndrome remains to be determined.

BDNF and Cerebellar Ataxia.

Brain-derived neurotrophic factor (BDNF) has been proposed as a treatment for neurodegeneration, including diseases of the cerebellum, where BDNF levels or those of its main receptor, TrkB, are often diminished relative to controls, thereby serving as replacement therapy. Experimental evidence indicates that BDNF signaling countered cerebellar degeneration, sensorimotor deficits, or both, in transgenic ATXN1 mice mutated for ataxin-1, Cacna1a knock-in mice mutated for ataxin-6, mice injected with lentivectors encoding RNA sequences against human FXN into the cerebellar cortex, Kcnj6Wv (Weaver) mutant mice with granule cell degeneration, and rats with olivocerebellar transaction, similar to a BDNF-overexpressing transgenic line interbred with Cacng2stg mutant mice. In this regard, this study discusses whether BDNF is effective in cerebellar pathologies where BDNF levels are normal and whether it is effective in cases with combined cerebellar and basal ganglia damage.

Probiotic Influences on Motor Skills: A Review.

The effects of probiotics have mostly been shown to be favorable on measures of anxiety and stress. More recent experiments indicate single- and multi-strain probiotics in treating motorrelated diseases. Initial studies in patients with Parkinson's disease and Prader-Willi syndrome are concordant with this hypothesis. In addition, probiotics improved motor coordination in normal animals and models of Parkinson's disease, multiple sclerosis, and spinal cord injury as well as grip strength in hepatic encephalopathy. Further studies should delineate the most optimal bacterial profile under each condition.

One-trial appetitive learning tasks for drug targeting.

One-trial appetitive learning developed from one-trial passive avoidance learning as a standard test of retrograde amnesia. It consists of one learning trial followed by a retention test, in which physiological manipulations are presented. As in passive avoidance learning, food- or water-deprived rats or mice finding food or water inside an enclosure are vulnerable to the retrograde amnesia produced by electroconvulsive shock treatment or the injection of various drugs. In one-trial taste or odor learning conducted in rats, birds, snails, bees, and fruit flies, there is an association between a food item or odorant and contextual stimuli or the unconditioned stimulus of Pavlovian conditioning. The odor-related task in bees was sensitive to protein synthesis inhibition as well as cholinergic receptor blockade, both analogous to results found on the passive avoidance response in rodents, while the task in fruit flies was sensitive to genetic modifications and aging, as seen in the passive avoidance response of genetically modified and aged rodents. These results provide converging evidence of interspecies similarities underlying the neurochemical basis of learning.

Neurobehavioral basis of Maier 3-table and other matching-to-place tasks.

The Maier 3-table task comprises three phases conducted each day. During the exploration phase, rats explore the entire apparatus. During the information phase, the rats are placed on one of the three tables where food is found. During the test phase, the animals are placed at the starting point on one of the two remaining tables and must enter the goal table where they previously ate. The acquisition of the Maier 3-table task was slowed down after lesions of the septum, fornix, hippocampus, medial prefrontal cortex, or posterior parietal cortex. Because of its time-consuming nature, the Maier 3-table task has more recently been superseded by appetitive matching-to-place in Y- or T-mazes or the circular water maze, because experimenters skip over the exploration phase. Nevertheless, like the Maier 3-table task, the acquisition of the Y- or T-maze matching-to-place task was retarded after lesions of the medial septum or medial prefrontal cortex, more particularly its prelimbic-infralimbic part. Like the previous task, the water-maze version is sensitive to lesions of the medial septum or retrosplenial cortex. Despite methodological differences between the three procedures, these results indicate common neurobiological bases of matching-to-place learning.

Cocoa Flavanols and the Aging Brain.

Partly because of its antioxidant and anti-inflammatory properties, cocoa flavanols have been examined in reversing age-related cognitive deficits. Epidemiological studies indicate a relation between flavonoid intake and the prevention of dementia. In confirmation of this relation, several pharmacological studies show the faster speed of responding and better executive performance in flavanol-treated aged or young subjects. The lack of any effect appears in some studies, especially in young subjects, perhaps due to the use of groups with high educational levels and the possibility of a ceiling effect. In several studies, neuropsychological ameliorations were followed by increases in cerebral blood flow. These results are in line with those of animal experimentation since improvements have been found in motor and spatial performances of young and aging mice or rats as well as animal models of Alzheimer's disease and Parkinson's disease. Improvements are also reported in biologic markers of Alzheimer's disease, in particular an increase in soluble Aß and a decrease in tau hyperphosphorylation.

The DST gene in neurobiology.

DST is a gene whose alternative splicing yields epithelial, neuronal, and muscular isoforms. The autosomal recessive Dstdt (dystonia musculorum) spontaneous mouse mutation causes degeneration of spinocerebellar tracts as well as peripheral sensory nerves, dorsal root ganglia, and cranial nerve ganglia. In addition to Dstdt mutants, axonopathy and neurofilament accumulation in perikarya are features of two other murine lines with spontaneous Dst mutations, targeted Dst knockout mice, DstTg4 transgenic mice carrying two deleted Dst exons, DstGt mice with trapped actin-binding domain-containing isoforms, and conditional Schwann cell-specific Dst knockout mice. As a result of nerve damage, Dstdt mutants display dystonia and ataxia, as seen in several genetically modified models and their motor coordination deficits have been quantified along with the spontaneous Dst nonsense mutant, the conditional Schwann cell-specific Dst knockout, the conditional DstGt mutant, and the Dst-b isoform specific Dst mutant. Recent findings in humans have associated DST mutations of the Dst-b isoform with hereditary sensory and autonomic neuropathies type 6 (HSAN-VI). These data should further encourage the development of genetic techniques to treat or prevent ataxic and dystonic symptoms.

Probiotic effects on anxiety-like behavior in animal models.

Gut microbiota have been shown to be useful in treating gastrointestinal diseases, cancer, obesity, infections, and, more recently, neuropsychiatric conditions such as degenerative diseases and depression. There has also been recent expansion in testing probiotics and prebiotics on anxiety-like behaviors in animals. Current results indicate that probiotic substances of the Lactobacillus and Bifidobacterium type are effective in reducing anxiety-like behaviors in mice or rats evaluated in the elevated plus-maze, the open-field, the light-dark box, and conditioned defensive burying. Probiotics are also effective in reducing serum or plasma corticosterone levels after acute stress. It is hypothesized that probiotics cause anxiolytic-like effects via vagal influences on caudal solitary nucleus, periaqueductal gray, central nucleus of the amygdala, and bed nucleus of the stria terminalis. Further experimentation is needed to trace the neurochemical anatomy underlying anxiolytic-like behaviors of gut microbiata exerting effects via vagal or nonvagal pathways.

The Hole-Board Test in Mutant Mice.

First described by Boissier and Simon in (Ther Recreat J 17:1225-1232, 1962), the hole-board has become a recognized test of anxiety and spatial memory. Benzodiazepines acting at the GABAA-BZD site increase hole-pokes in rats and mice, indicating a loss in behavioral inhibition concordant with the behavior of mutant mice deficient in the GABA transporter. Hole-poking also depends on arousal mechanisms dependent on dopaminergic transmission, as indicated by drug and null mutant studies. In addition, the behavior is modified in natural and null mutants affecting the cerebellum as well as null mutants affecting neuropeptides, growth factors, cell adhesion, and inflammation. Further research is required to determine convergences between genetic and pharmacological effects.

Neurochemical anatomy of dorsal and tonic immobility responses.

The dorsal immobility response (DIR) and the tonic immobility response (TIR) are cutaneo-motor reflexes typically triggered when a prey is seized. The neurochemical basis of the DIR appears to pass through the basal ganglia via dopaminergic fibers, while the neurochemical basis of the TIR appears to include a circuit comprising the amygdala, the periaqueductal gray (PAG), the dorsal raphe, and the nucleus magnus raphe (NMR) via glutamatergic, serotonergic, cholinergic, GABAergic, and opioid fibers. For the DIR, the basal ganglia also seem to be involved in regard to estradiol, while for the TIR, the HPA axis appears involved at the level of the amygdala and the oral pontine reticular nucleus.

The mouse at the popcorn stage of development.

In mice, rats, and rabbits, vigorous jumping and hyperexcitability occur at the popcorn stage of postnatal development. In view of subcortical structures appearing before cortical ones, the trait is deemed to occur at the maturation time of ascending excitatory projections from the brainstem and to disappear at the maturation time of descending inhibitory projections from the forebrain. There is evidence that the popcorn stage may be due in part to the lack of a cholinergic influence on dopamine systems. Based mostly on results found in adult mice and rats, there may also be a role for cortico-subcortical systems that include the cerebellum and basal ganglia requiring the influence of biogenic amines, glutamate, and endocannabinoids.

The Herc1 gene in neurobiology.

The function of the HERC1 gene has mainly been delineated by studying Herc1tbl (tambaleante) mutant mice, characterized by losses in cerebellar Purkinje cells, a lower number of synaptic vesicles in the hippocampus, and anomalies in climbing fiber projections from the inferior olive as well as alpha-motoneuron projections to the skeletal muscle. The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, muscle weakness, and spatial deficits. Similar neuropathological and behavioral profiles have been described in childhood-onset subjects with HERC1 variants, including cerebellar ataxia and hypotonia.

The AGTPBP1 gene in neurobiology.

The function of the Agtpbp1 gene has mainly been delineated by studying Agtpbp1pcd (pcd) mutant mice, characterized by losses in cerebellar Purkinje and granule cells along with degeneration of retinal photoreceptors, mitral cells of the olfactory bulb, thalamic neurons, and alpha-motoneurons. As a result of cerebellar degeneration, cerebellar GABA and glutamate concentrations in Agtpbp1pcd mutants decreased while monoamine concentrations increased. The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, and cognitive deficits. Similar neuropathogical and behavioral profiles have been described in childhood-onset human subjects with biallelic variants of AGTPBP1, including cerebellar ataxia and hypotonia.

SHIRPA as a Neurological Screening Battery in Mice.

The SmithKline, Harwell, Imperial College, Royal Hospital, Phenotype Assessment (SHIRPA) is a rapid battery of tests comprising 42 measurements of motor activity, coordination, postural control, muscle tone, autonomic functions, and emotional reactivity, as well as reflexes dependent on visual, auditory, and tactile modalities. Individual scores in SHIRPA are sensitive in detecting phenotypes of several experimental models of neural disease, especially cerebellar degeneration and Alzheimer disease, and combined subscores have been useful in estimating the impact of vascular anomalies and exposure to infectious agents. In cerebellar degeneration, weak forelimb grip, impaired wire maneuver and air righting, and negative geotaxis appear as prevalent features. Most of the measures in the battery are susceptible to change after gene modifications or physiological alterations. SHIRPA can be used both in adult mice and mice in the preweaning period to screen for sensorimotor function and emotional reactivity, not selective attention or memory. © 2021 Wiley Periodicals LLC Basic Protocol: Step-by-step procedure for SHIRPA.

Effects of corticosterone injections in mid-to-late mouse postnatal development on adult motor activity and coordination.

Glucocorticoids are involved in the developing brain but, in excessive amounts, may depress its growth and cause psychomotor development disorders. To test the long-term vulnerability of motor structures such as the cerebellum to supraphysiological corticosterone (CORT), the hormone was subcutaneously delivered at a dose of 20 mg/kg from postnatal day (P) 8 to P29 in C57BL/6 male mice evaluated for sensorimotor functions at P15, P22, P29, and 3 months. Relative to placebo, CORT increased motor activity in the open-field at P29 and 3 months as well as facilitating rotorod acquisition and visuomotor control necessary for swimming towards a visible goal without affecting spatial learning in the Morris water maze. CORT caused lobule-specific effects on cerebellar morphology by decreasing granule cell layer thickness in simplex lobule but increasing molecular and granule cell layer thickness in crus 2. The functional impact of these changes is indicated by significant correlations found between cerebellar size and activity levels or proficiency on the rotorod test of motor coordination.

Efficacy, tolerability, and safety of an innovative medical device for improving oral accessibility during oral examination in special-needs patients: A multicentric clinical trial.

BACKGROUND: People with special needs have high unmet oral healthcare needs, partly because dentists find it difficult to access their oral cavity. The Oral Accessibility Spatula aims to improve oral accessibility. This prospective multicenter interventional open-label non-randomized patient-self-controlled trial assessed the ability of the spatula to improve the oral accessibility of special-needs patients during dental examinations. METHODS: The cohort was a convenience sample of minor and adult patients with special needs due to physical, intellectual, and/or behavioral disorders who underwent dental check-up/treatment in five French tertiary hospitals/private clinics in 2016-2018 and evinced some (Venham-Score = 2-4) but not complete (Venham-Score = 5) resistance to oral examination. After inclusion, patients underwent oral examination without the spatula and then immediately thereafter oral examination with the spatula. Primary outcome was Oral Accessibility Score (0-12 points; higher scores indicate visualization and probing of the tooth sectors). Secondary outcomes were patient toleration (change in Venham-Score relative to first examination), safety, and Examiner Satisfaction Score (0-10; low scores indicate unsatisfactory examination). RESULTS: The 201 patients were mostly non-elderly adults (18-64 years, 65%) but also included children (21%), adolescents (11%), and aged patients (3%). One-quarter, half, and one-quarter had Venham-Score = 2, 3, and 4 at inclusion, respectively. The spatula significantly improved Oral Accessibility Score (4.8 to 10.8), Venham-Score (3.1 to 2.6), and Examiner Satisfaction Score (3.4 to 7.2) (all p<0.001). There were no severe spatula-related adverse events. CONCLUSION: The spatula significantly improved oral access, was safe and well-tolerated by the patients, and markedly improved oral examination quality.

Motor Performances of Spontaneous and Genetically Modified Mutants with Cerebellar Atrophy.

Chance discovery of spontaneous mutants with atrophy of the cerebellar cortex has unearthed genes involved in optimizing motor coordination. Rotorod, stationary beam, and suspended wire tests are useful in delineating behavioral phenotypes of spontaneous mutants with cerebellar atrophy such as Grid2Lc, Grid2ho, Rorasg, Agtpbp1pcd, Relnrl, and Dab1scm. Likewise, transgenic or null mutants serving as experimental models of spinocerebellar ataxia (SCA) are phenotyped with the same tests. Among experimental models of autosomal dominant SCA, rotorod deficits were reported in SCA1 to 3, SCA5 to 8, SCA14, SCA17, and SCA27 and stationary beam deficits in SCA1 to 3, SCA5, SCA6, SCA13, SCA17, and SCA27. Beam tests are sensitive to experimental therapies of various kinds including molecules affecting glutamate signaling, mesenchymal stem cells, anti-oligomer antibodies, lentiviral vectors carrying genes, interfering RNAs, or neurotrophic factors, and interbreeding with other mutants.

Neuroanatomical pathways underlying the effects of hypothalamo-hypophysial-adrenal hormones on exploratory activity.

When injected via the intracerebroventricular route, corticosterone-releasing hormone (CRH) reduced exploration in the elevated plus-maze, the center region of the open-field, and the large chamber in the defensive withdrawal test. The anxiogenic action of CRH in the elevated plus-maze also occurred when infused in the basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex. The anxiogenic action of CRH in the defensive withdrawal test was reproduced when injected in the locus coeruleus, while the amygdala, hippocampus, lateral septum, nucleus accumbens, and lateral globus pallidus contribute to center zone exploration in the open-field. In addition to elevated plus-maze and open-field tests, the amygdala appears as a target region for CRH-mediated anxiety in the elevated T-maze. Thus, the amygdala is the principal brain region identified with these three tests, and further research must identify the neural circuits underlying this form of anxiety.

Repeated corticosterone injections in adult mice alter stress hormonal receptor expression in the cerebellum and motor coordination without affecting spatial learning.

Receptors for glucocorticoid (GR) and corticotropin-releasing hormone (CRH) are largely found in brain sensorimotor structures, particularly in cerebellum, underlining a potential role of stress hormones in the regulation of motor function. Since CRH is involved in neuroplasticity, known for its trophic effect on synapses, we investigated how manipulations in corticosterone serum levels can modulate the CRH system in the cerebellum and affect motor coordination. Corticosterone at doses of either 15 or 30mg/kg was injected in mice and the status of hormonal expression evaluated in cerebellum, hippocampus, and hypothalamus in undisturbed housing conditions or after different behavioral tests. Under both conditions, metabolic activity in numerous brain regions involved in motor functions and emotion was measured by means of cytochrome oxidase (COX) activity labeling. After six consecutive days of corticosterone administration, CRH-R1 transcription was downregulated in hypothalamic and cerebellar regions and hypometabolic changes were observed in mice treated with the higher dose for several limbic and sensorimotor circuitries, notably basal ganglia, deep cerebellar nuclei, and red nucleus. Corticosterone did not modify motor activity, anxiety, and spatial orientation, but decreased latencies before falling from the rotorod and prevented mice from reaching targets in the coat-hanger test. In addition, COX activities were similar to control mice except in ventromedial thalamus and dorsal neostriatum, possibly indicating that physical activity protected brain energy metabolism against the stress hormone. The present findings showed that the CRH/CRH-R1 system might play a role in mediating the effects of stress on cerebellar function, affecting especially motor learning tasks.