Corticosterone effects on postnatal cerebellar development in mice.

Glucocorticoids administered early in infancy can affect the architectonic organization of brain structures, particularly those with a postnatal development and resulting in long-term deficits of neuromotor function and cognition. The present study was undertaken to study the effects of daily corticosterone (CORT) injections at a pharmacological dose from postnatal days 8-15 on cerebellar and hippocampal development in mouse pups. Gene expression status for trophic factors involved in synaptic development and function as well as measures of layer thickness associated with cytochrome oxidase labelling were analyzed in the hippocampus, hypothalamus, and specific cerebellar lobules involved in motor control. Repeated CORT injections dysregulated the HPA axis with increased Crh and Nr3c1 mRNA levels in the hypothalamus and a resulting higher serum corticosterone level. The CORT treatment altered the morphology of the hippocampus and down-regulated gene transcription for corticotropin-releasing hormone (Crh) and its type-1 receptor (Crhr1), glucocorticoid receptor (Nr3c1), and brain-derived neurotrophic factor Bdnf and its receptor Ntrk2 (neurotrophic receptor tyrosine kinase 2). Similar mRNA expression decreases were found in the cerebellum for Crhr1, Crhr2, Nr3c1, and Grid2 (glutamatergic δ2 receptor). Morphological alterations and metabolic activity variations were observed in specific cerebellar lobules involved in motor control. The paramedian lobule, normally characterized by mitotic activity in the external germinative layer during the second postnatal week, was atrophic but metabolically hyperactive in its granule cell and molecular layers. On the contrary, lobules with an earlier cell proliferation displayed neurogenesis but a hypoactivated granule cell layer, suggesting a developmental delay in synaptogenesis. The results indicate that glucocorticoid, administered daily during the second postnatal week modulated the developmental programming of the hippocampus and cerebellum. These growth and metabolic alterations may lead possibly to morphological and functional changes later in life.

Behavioral and neurochemical effects of dietary methyl donor deficiency combined with unpredictable chronic mild stress in rats.

Methyl donor deficiencies and chronic stress cause depression independently, but their interaction has never been thoroughly evaluated. In our study, methyl donor deficient diet and chronic stress condition consisted respectively of a B2, B9, B12, and choline-free diet and a chronic mild stress procedure. Rats were randomly assigned to six groups with three "diet" conditions (free-feeding, pair-fed and methyl donor deficient diet) and two "stress" conditions (no-stress and stress) and were evaluated in the open-field, the elevated plus-maze and the forced swimming test. After the behavioral evaluation, corticosterone and homocysteine plasma levels were measured and dopamine, DOPAC, serotonin, 5HIAA concentrations were evaluated in several brain areas. Rats given a methyl donor deficient diet for 11 weeks causing elevated plasma homocysteine levels were compared to pair-fed and free-feeding rats with or without unpredictable chronic mild stress. Regardless of stress environmental conditions, the methyl donor deficient diet decreased plasma corticosterone levels and caused disinhibition in the elevated plus-maze condition relative to both control groups. However, stress potentiated the effects of the deficient regimen on rearing in the open-field and climbing in the forced swim test. The dietary changes involved in behavior and plasma corticosterone could be caused by homocysteine-induced decreases in dopamine and 5-hydroxytryptamine metabolites in selective brain regions and it can be noted that regardless of stress-conditions, methyl donor deficient diet decreases DOPAC/dopamine and 5HIAA/serotonin ratios in striatum and hypothalamus and selectively 5HIAA/serotonin ratio in the sensorimotor cortex. Our experimental data is particularly relevant in the context of neuropsychiatric disorders frequently associated with folate deficiency and hyperhomocysteinemia.

Neurobehavioral performances and brain regional metabolism in Dab1(scm) (scrambler) mutant mice.

As disabled-1 (DAB1) protein acts downstream in the reelin signaling pathway modulating neuronal migration, glutamate neurotransmission, and cytoskeletal function, the disabled-1 gene mutation (scrambler or Dab1(scm) mutation) results in ataxic mice displaying dramatic neuroanatomical defects similar to those observed in the reeler gene (Reln) mutation. By comparison to non-ataxic controls, Dab1(scm) mutants showed severe motor coordination impairments on stationary beam, coat-hanger, and rotorod tests but were more active in the open-field. Dab1(scm) mutants were also less anxious in the elevated plus-maze but with higher latencies in the emergence test. In mutants versus controls, changes in regional brain metabolism as measured by cytochrome oxidase (COX) activity occurred mainly in structures intimately connected with the cerebellum, in basal ganglia, in limbic regions, particularly hippocampus, as well as in visual and parietal sensory cortices. Although behavioral results characterized a major cerebellar disorder in the Dab1(scm) mutants, motor activity impairments in the open-field were associated with COX activity changes in efferent basal ganglia structures such as the substantia nigra, pars reticulata. Metabolic changes in this structure were also associated with the anxiety changes observed in the elevated plus-maze and emergence test. These results indicate a crucial participation of the basal ganglia in the functional phenotype of ataxic Dab1(scm) mutants.

Brain regions and genes affecting myoclonus in animals.

Myoclonus is defined as large-amplitude rhythmic movements. Brain regions underlying myoclonic jerks include brainstem, cerebellum, and cortex. Gamma-aminobutyric acid (GABA) appears to be the main neurotransmitter involved in myoclonus, possibly interacting with biogenic amines, opiates, acetylcholine, and glycine. Myoclonic jumping is a specific subtype seen in rodents, comprising rearing and hopping continuously against a wall. Myoclonic jumping can be seen in normal mouse strains, possibly as a result of simply being put inside a cage. Like other types, it is also triggered by changes in GABA, 5HT, and dopamine neurotransmission. Implicated brain regions include hippocampus and dorsal striatum, possibly with respect to D(1) dopamine, NMDA, and δ opioid receptors. There is reason to suspect that myoclonic jumping is underreported due to insufficient observations into mouse cages.

Abnormal grooming activity in Dab1(scm) (scrambler) mutant mice.

Dab1(scm) mutant mice, characterized by cell ectopias and degeneration in cerebellum, hippocampus, and neocortex, were compared to non-ataxic controls for different facets of grooming caused by brief water immersions, as well as some non-grooming behaviors. Dab1(scm) mutants were strongly affected in their quantitative functional parameters, exhibiting higher starting latencies before grooming relative to non-ataxic littermates of the A/A strain, fewer grooming bouts, and grooming components of shorter duration, with an unequal regional distribution targeting almost totally the rostral part (head washing and forelimb licking) of the animal. Only bouts of a single grooming element were preserved. The cephalocaudal order of grooming elements appeared less disorganized, mutant and control mice initiating the grooming with head washing and forelimb licking prior to licking posterior parts. However, mutants differed from controls in that all their bouts were incomplete but uninterrupted, although intergroup difference for percentage of the incorrect transitions was not significant. In contrast to grooming, Dab1(scm) mice ambulated for a longer time. During walking episodes, they exhibited more body scratching than controls, possibly to compensate for the lack of licking different body parts. In conjunction with studies with other ataxic mice, these results indicate that the cerebellar cortex affects grooming activity and is consequently involved in executing various components, but not in its sequential organization, which requires other brain regions such as cerebral cortices or basal ganglia.

APP transgenic mice for modelling behavioural and psychological symptoms of dementia (BPSD).

The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aß accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioural and psychological symptoms of Alzheimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine.

Spontaneous alternation and spatial learning in Dab1scm (scrambler) mutant mice.

Homozygous Dab1scm mutants with cell ectopias in cerebellar cortex, hippocampus, and neocortex were compared with non-ataxic heterozygous and wild-type controls in spontaneous alternation and Morris water maze tests. Although there were no group differences in alternation rates, wild-type and heterozygote groups alternated above chance levels, whereas homozygous Dab1scm mutants did not. In the Morris water maze, Dab1scm mutants were impaired in both hidden and visible platform subtests. The deficits in spontaneous alternation and water maze measures reproduce the phenotype previously described in Reln(rl-Orl) mutants, attributed to disturbance of the same molecular pathway involving reelin.

Acetylcholinesterase activity in the brain of dystonia musculorum (Dst(dt-J)) mutant mice.

The dystonia musculorum (Dst(dt-J)) mutant mouse suffers from severe motor coordination deficits, characterized, among various symptoms, by a spastic ataxia and dystonic movements, indicating central defects in motor structures in addition to dystrophy of peripheral sensory tracts and partial degeneration of spinocerebellar tracts. Neurochemical alterations, notably in dopaminergic and noradrenergic systems, were previously observed in basal ganglia and cerebellum. A quantitative histochemical cartography of brain acetylcholinesterase activity in Dst(dt-J) mutants, in comparison with controls, revealed increases in the neostriatum, the habenula-interpeduncular pathway, the cholinergic pedunculopontine nucleus and its target structures, the thalamus, major regions of the basal ganglia, such as substantia nigra, ventral tegmental area, globus pallidum, and subthalamic nucleus, as well as in associated extrapyramidal regions, such as red nucleus, brainstem reticular formation, and superior colliculus. These acetylcholinesterase changes may play a role in motor deficits, particularly the dystonic symptomatology observed in the mutation.

Neurologic function during developmental and adult stages in Dab1(scm) (scrambler) mutant mice.

Homozygous Dab1(scm) mouse mutants with cell ectopias in cerebellar cortex, hippocampus, and neocortex were compared to non-ataxic controls on the SHIRPA primary screening battery on postnatal days 8, 15, and 22, as well as in the adult period. Dab1(scm) mutants were distinguished from non-ataxic controls as early as postnatal day 8 based on body tremor, gait anomalies, and body weight. On postnatal day 15, motor coordination deficits were evident on horizontal bar and inclined or vertical grid tests in association with a weaker grip strength. Likewise, mutants were distinguished from controls on drop righting and hindpaw clasping tests. Further differences were detected on postnatal day 22 in the form of fewer visual placing, touch escape, trunk curl, freezing, and vocalization responses, as well as squares traversed in the open-field. Evaluation at the adult age demonstrated similar impairments, indicative of permanent motor alterations. Neuronal metabolic activity was estimated by cytochrome oxidase histochemistry on cerebellar sections. Cerebellar cortical layers and efferent deep nuclei of Dab1(scm) mice appeared hypometabolic relative to non-ataxic mice despite normal metabolism in both regular and ectopic Purkinje cells.

Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6JIco and BALB/cAnN@Ico mice injected with ethanol.

The effects of ethanol were examined on three tests of exploratory activity in two mouse strains. Although ethanol reduced open-field rearing in both strains, it increased ambulation only in the less active BALB/cAnN@Ico strain, not in the C57BL/6JIco strain. Likewise, ethanol increased open and enclosed arm entries in the elevated plus-maze only in the more anxious BALB/cAnN@Ico strain. However, both strains injected with ethanol emerged faster than placebo from a small chamber at doses not affecting behaviors in the other two tests. Significant correlations were found between emergence latencies on one hand and either slow stereotyped movements or open and enclosed arm entries on the other. The strain-specific effects may be attributable to differences in GABA(A) -related receptor binding or catalase activity.

Brain regions and genes affecting limb-clasping responses.

Adult rodents picked up by the tail and slowly descending towards a horizontal surface extend all four limbs in anticipation of contact. Mouse mutants with pathologies in various brain regions and the spinal cord display instead a flexion response, often characterized by paw-clasping and a bat-like posture. These phenotypes are observed in mice with lesions in cerebellum, basal ganglia, and neocortex, as well as transgenic models of Alzheimer's disease. The underlying mechanism appears to include cerebello-cortico-reticular and cortico-striato-pallido-reticular pathways, possibly triggered by changes in noradrenaline and serotonin transmission.

Sensorimotor learning in Dab1(scm) (scrambler) mutant mice.

Homozygous Dab1(scm) mouse mutants with cell ectopias in cerebellar cortex and neocortex were compared with non-ataxic controls on two tests of motor coordination: rotorod and grid climbing. Even at the minimal speed of 4 rpm and unlike controls, none of the Dab1(scm) mutants reached criterion on the constant speed rotorod. In contrast, Dab1(scm) mutants improved their performances on the vertical grid over the course of the same number of trials. Thus, despite massive cerebellar degeneration, sensorimotor learning for equilibrium is still possible, indicating the potential usefulness of the grid-climbing test in determining residual functions in mice with massive cerebellar damage.

The relation between open-field and emergence tests in a hyperactive mouse model.

The relation between open-field and emergence tests was examined in mice with idiopathic hypertension. Spontaneous hypertensive mice (SHM) crossed more segments and reared more often in the open-field than normotensive controls at both age levels. In contrast, grooming episodes decreased only in the older SHM cohort. While young SHM emerged more quickly from a toy object only partially, complete emergence was faster only in the older SHM cohort. In the entire series, open-field segments were inversely correlated with 2- and 4-paw emergence latencies. There was also an inverse correlation between rears and 2-paw emergence but a positive correlation between grooming episodes and both types of emergence. In view of its association with open-field activity, the emergence test may have value in screening potential ADHD therapies.

Regional brain evaluation of acetylcholinesterase activity in PS1/A246E transgenic mice.

Human presenilin-1 (PS1) mutations are a major cause of autosomal dominant Alzheimer's disease. Forebrain cholinergic innervation was estimated in transgenic mice with the A246E mutation by measuring the activity of the non-specific catabolic enzyme, acetylcholinesterase (AChE). In the model, Abeta(42) concentrations increase without neuritic plaques or cell degeneration. PS1/A246E transgenic mice had altered AChE activity in several regions also vulnerable in Alzheimer pathology. In particular, AChE activity was upregulated in major cholinergic cell nuclei (medial septum, vertical diagonal band, substantia inominata) and in cortical and thalamic regions (eye field, posterior parietal and visual cortices, posterior thalamic and lateral geniculate nuclei) responsible for selective attention and visuomotor coordination, as well as limbic structures (hippocampal formation and amygdala) with related regions (midline, periventricular, reticular thalamic nuclei, and lateral prefrontal, agranular insular cortices) involved in cognition, arousal, emotion, and plasticity. As the murine model caused no apparent learning defects, cholinergic network changes in forebrain seem to be an early event caused by soluble Abeta peptides. PS1/A246E mice mimic to some extent pre-symptomatic Alzheimer's disease neuropathology, useful for studying early neurochemical changes often inaccessible in clinical studies.

Exploratory activity and motor coordination in old versus middle-aged C57BL/6J mice.

Aged mice were compared to middle-aged mice in two tests of exploratory activity and two tests of motor coordination. The 16-month-old mice had more ambulatory and rearing movements than 24-month-old mice, but fewer stereotyped movements. In contrast, no difference was found in the emergence test. The 16-month-old group outperformed the 24-month-old group on the stationary beam and coat-hanger tests. Regression analyses indicate that the number of falls from the stationary beam was positively correlated with movement times (MTs) before reaching the end of the horizontal bar. However, there was no significant correlation between open-field measures and emergence latencies, indicating that the two tests of exploratory activity estimate separate aspects of behavior.

Discrimination learning in Rora(sg) and Grid2(ho) mutant mice.

Rora(sg) mutants with mild cerebellar granule cell degeneration were compared to Grid2(ho) mutants with more severe granule cell degeneration as well as Purkinle cell atrophy for left-right and dark-light discrimination learning tasks in a water-filled T-maze. The acquisition rate of both cerebellar mutants was slowed down during light-dark but not left-right discrimination learning. However, the mutants were impaired in reversal training in both tasks. In contrast, neither mutant differed from controls in passive avoidance learning. These results indicate that mice with cerebellar damage are affected in some instrumental learning tasks and have perseverative tendencies.

Relations between open-field, elevated plus-maze, and emergence tests as displayed by C57/BL6J and BALB/c mice.

The relations between open-field, elevated plus-maze, and emergence tests were examined in two strains of mice. In the open-field, C57BL/6J mice had more ambulatory movements and rears but not stereotyped movements relative to BALB/c. In addition, C57BL/6J mice entered more often than BALB/c into enclosed and open arms of the elevated plus-maze. When placed inside a large enclosure, C57BL/6J mice emerged more quickly than BALB/c from a small toy object. In the entire series of mice, ambulation and rears in the open-field were linearly correlated with open and enclosed arm visits in the elevated plus-maze. Ambulatory movements and rears were also correlated with emergence latencies. In contrast, stereotyped movements were correlated with emergence latencies, but not with any elevated plus-maze value. These results specify the extent and limits of association between the three tests.

Effects of a B-vitamin-deficient diet on exploratory activity, motor coordination, and spatial learning in young adult Balb/c mice.

Elevated homocysteine levels resulting from vitamin B deficiencies have been hypothesized to contribute to functional decline. To investigate the effects of elevated serum homocysteine on neurobehavioral performances, young adult Balb/c mice consumed a vitamin-B-deficient diet or a control diet under free-feeding and pair-fed conditions. The B-deficient diet decreased body weight and food intake but increased water ingestion. Relative to either control group, vitamin-B-deficient mice were more active in the open field and in enclosed arms of the elevated plus-maze. However, vitamin-B-deficient mice were not impaired on sensorimotor coordination and spatial learning tests, swimming to a visible platform even faster than either control group. The main effect of this diet restriction was hyperactivity with no change in anxiety, coordination, and memory. It remains to be determined whether severer deficits are demonstrable in older mice.

Regional variations of cytochrome oxidase activity in the central auditory system of Relnrl-Orl (reeler) mutant mice.

Despite preserved cell differentiation, the Reln(rl-Orl) phenotype comprises laminar abnormalities of cell position in auditory cortex and dorsal cochlear nucleus. The metabolic consequences of the cell ectopias were determined by estimating cytochrome oxidase (CO) activity, a marker of neuronal activity. CO activity increased in the granular cell layer of dorsal cochlear nucleus, trapezoid body nucleus, intermediate lateral lemniscus, central and external inferior colliculus, and pyramidal cell layer of primary auditory cortex. On the contrary, CO activity decreased in the superficial molecular layer of dorsal cochlear nucleus as well as in the medioventral periolivary nucleus. These metabolic variations are discussed in terms of their possible relation to morphologic anomalies observed in the mutant.

Brain regions and genes affecting postural control.

Postural control is integrated in all facets of motor commands. The role of cortico-subcortical pathways underlying postural control, including cerebellum and its afferents (climbing, mossy, and noradrenergic fibers), basal ganglia, motor thalamus, and parieto-frontal neocortex has been identified in animal models, notably through the brain lesion technique in rats and in mice with spontaneous and induced mutations. These studies are complemented by analyses of the factors underlying postural deficiencies in patients with cerebellar atrophy. With the gene deletion technique in mice, specific genes expressed in cerebellum encoding glutamate receptors (Grid2 and Grm1) and other molecules (Prkcc, Cntn6, Klf9, Syt4, and En2) have also been shown to affect postural control. In addition, transgenic mouse models of the synucleinopathies and of Huntington's disease cause deficiencies of motor coordination resembling those of patients with basal ganglia damage.