Intersession Habituation Research Articles

PA28\u03b1\u03b2 overexpression enhances learning and memory of female mice without inducing 20S proteasome activity

BackgroundThe proteasome system plays an important role in synaptic plasticity. Induction and maintenance of long term potentiation is directly dependent on selective targeting of proteins for proteasomal degradation. The 20S proteasome activator PA28αβ activates hydrolysis of small nonubiquitinated peptides and possesses protective functions upon oxidative stress and proteinopathy. The effect of PA28αβ activity on behavior and memory function is, however, not known. We generated a mouse model that overexpresses PA28α (PA28αOE) to understand PA28αβ function during healthy adult homeostasis via assessment of physiological and behavioral profiles, focusing on female mice.ResultsPA28α and PA28β protein levels were markedly increased in all PA28αOE tissues analyzed. PA28αOE displayed reduced depressive-like behavior in the forced swim test and improved memory/learning function assessed by intersession habituation in activity box and shuttle box passive avoidance test, with no significant differences in anxiety or general locomotor activity. Nor were there any differences found when compared to WT for body composition or immuno-profile. The cognitive effects of PA28αOE were female specific, but could not be explained by alterations in estrogen serum levels or hippocampal regulation of estrogen receptor β. Further, there were no differences in hippocampal protein expression of neuronal or synaptic markers between PA28αOE and WT. Biochemical analysis of hippocampal extracts demonstrated that PA28α overexpression did not increase PA28–20S peptidase activity or decrease K48-polyubiquitin levels. Instead, PA28αOE exhibited elevated efficiency in preventing aggregation in the hippocampus.ConclusionsThis study reveals, for the first time, a connection between PA28αβ and neuronal function. We found that PA28α overexpressing female mice displayed reduced depressive-like behavior and enhanced learning and memory. Since the positive effects of PA28α overexpression arose without an activation of 20S proteasome capacity, they are likely independent of PA28αβ’s role as a 20S proteasome activator and instead depend on a recognized chaperone-like function. These findings suggest that proteostasis in synaptic plasticity is more diverse than previously reported, and demonstrates a novel function of PA28αβ in the brain.

Locomotor activity, emotionality, sensori-motor gating, learning and memory in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

The APPswe/PS1dE9 mouse (line 85) is a double transgenic model of Alzheimer’s disease (AD) with familial amyloid precursor protein and presenilin-1 mutations. These mice develop age-related behavioral changes reflective of the neuropsychiatric symptoms (altered anxiety-like behaviour, hyperactivity) and cognitive dysfunction (impaired learning and memory) observed in AD. The APPswe/PS1dE9 mouse has been used to examine the efficacy of therapeutic interventions on behaviour, despite previous difficulties in replicating behavioural phenotypes. Therefore, the purpose of this study was to establish the reliability of these phenotypes by further characterizing the behaviour of male APPswe/PS1dE9 and wild-type mice between 7 and 14 months of age. Mice were tested on the open-field over 5-days to examine emotionality, locomotor activity and inter-session habituation. Mice were also tested on the repeated-reversal water maze task and spontaneous alternation on the Y-maze to assess working memory. Sensori-motor gating was examined with acoustic startle and pre-pulse inhibition. Lastly contextual and cued (trace) memory was assessed with fear conditioning. The results show that among non-cognitive behaviours, APPswe/PS1dE9 mice have normal locomotor activity, anxiety-like behavior, habituation and sensori-motor gating. However, APPswe/PS1dE9 mice show impaired working memory on the repeated-reversal water-maze and impaired memory in contextual but not trace-cued fear conditioning. These results indicate that the APPswe/PS1dE9 (line 85) mice have deficits in some types of hippocampal-dependent learning and memory and, at the ages tested, APPswe/PS1dE9 mice model cognitive dysfunction but not neuropsychiatric symptoms.

The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats.

A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.

Effects of Cognitive-Behavioral Therapy on Brain Responses to Subliminal and Supraliminal Threat and Their Functional Significance in Specific Phobia

Neurocircuitry models of anxiety disorders suggest dysregulated mechanisms encompassing both automatic and elaborate threat processing. However, the extent to which these processes might be differentially modified by psychotherapy and the neural basis of such changes are unknown. We examined the effects of cognitive-behavioral therapy (CBT) in patients with anxiety disorder on brain responses to subliminal and supraliminal threat. 3-Tesla functional magnetic resonance imaging was used to assess neural responses to disorder-related stimuli, presented during two backward-masking conditions employed to manipulate stimulus awareness. In 28 spider-phobic patients randomly assigned to a therapy group or a waiting-list control group scanning was performed before and after completing CBT or a waiting period. Scanning was performed one time in 16 healthy control subjects. Self-report and behavioral measures were used to relate CBT-mediated brain activation changes with symptom improvement. Untreated patients demonstrated abnormal hyperactivation in the amygdala, fusiform gyrus, insula, anterior cingulate cortex, and dorsomedial prefrontal cortex. Successful CBT was reflected in an overall downregulation in these fear circuitry structures, especially in the right amygdala and anterior cingulate cortex, with reductions in amygdala responsiveness associated with self-reported symptom improvement. However, subliminal threat induced a pattern of right-lateralized hyperactivation in the amygdala and fusiform gyrus that was subject to intersession habituation across groups without showing significant sensitivity to CBT. These results challenge prevailing models that emphasize a role for amygdala automaticity in the maintenance of anxiety. Our results suggest CBT-related changes in neural activation associated with fear responses to consciously perceived threat.

Napping promotes inter-session habituation to emotional stimuli

The effects of a daytime nap on inter-session habituation to aversive visual stimuli were investigated. Healthy young adult volunteers viewed repeated presentations of highly negative and emotionally neutral (but equally arousing) International Affective Picture System (IAPS) photographs during two afternoon sessions separated by 2.5 h. Half of the photographs were shown at both sessions (Repeated Sets) and half differed between sessions (Novel Sets). For each stimulus presentation, evoked skin conductance response (SCR), heart-rate deceleration (HRD) and corrugator supercilii EMG response (EMG), were computed and range corrected using respective maximum session-1 responses. Following each presentation, subjects rated each photograph on dimensions of pleasantness and arousability. During the inter-session interval, Nap subjects had a 120-min polysomnographically monitored sleep opportunity, whereas Wake subjects watched a non-stimulating video. Nap and Wake subjects did not differ in their subjective ratings of photographs. However, for Repeated-Set photographs, Nap subjects demonstrated greater inter-session habituation in SCR and EMG but a trend toward lesser inter-session habituation in HRD. These group differences were absent for Novel-Set photographs. Group differences across all measures were greater for negative stimuli. Occurrence of SWS during the nap was associated with greater inter-session habituation of EMG whereas occurrence of REM was associated with lesser inter-session habituation of SCR to negative stimuli. Sleep may therefore promote emotional adjustment at the level of somatic responses. Physiological but not subjective inter-session habituation to aversive images was enhanced by a daytime nap.

Ageing or NOT, clock genes are important for memory processes: an interesting hypothesis raising many questions

Memory processes, such as acquisition, consolidation and retrieval are temporally regulated events. An intrinsic circadian (circa: about; dies: day) timing system influencing the dynamics in memory processing has been detected in animal models, ranging from invertebrates to mammalian species. Several recent investigations, addressing the molecular mechanism behind the circadian modulation of mnemonic processes shed light onto pathways known to be essential in memory processing, such as the cAMP-CREB-MAPK-pathway, which by itself is regulated by the circadian system. Notable, an important role for rhythmic clock gene expressions in the hippocampus and in hippocampus-dependent memory processes has been recently detected. However, the link between the circadian gating of memory processes and its importance for daily life remain highly elusive. In the here presented work [1], Kondratova and co-workers approached the possible effects of on cognitive performances, with the experimental design taking the known parallel decline in functional integrity of the circadian system and cognitive performance into account. For this purpose, the authors used 3-4 months old mice that are deficient for central clock genes, and thus, no longer exhibit circadian rhythms. Importantly, among the mice used, was the Bmal1-deficient mouse strain, known for its accelerated phenotype. Kondratova and co-workers observed that behaviors, such as habituation to a novel environment were altered in mice with deficiencies/mutations of core clock genes. Habituation to a novel environment can be considered a form of non-associative learning, and is dependent on (a) hippocampus-dependent working memory, a form of short-term memory with regards to intra-session habituation and (b) long-term memory for inter-session habituation. Bmal1- and Clock-knockout mice showed deficiencies in both types of habituation in contrast to Cry1/2-deficient mice that demonstrated facilitated habituation. The authors also proved by using an open field test that elevated anxiety, which often correlates with high locomotor activity and rearing, and deficits in contextual habituation does not attribute to deficits in behavioral learning in the here used clock-gene-knockout mice: Cry1,2-knockout mice showed facilitated habituation in parallel to elevated levels of anxiety, while Bmal1-knockout mice showed deficits in contextual habituation at significantly lower anxiety levels. The presented results confirm that a disruption of circadian clockwork impairs or facilitates in parallel the intra- and inter-session contextual habituation of mice. This observation acknowledges an essential regulatory role of core clock gene proteins in the herein analyzed behaviors, and thus in memory processes. If this is the case, then the interesting hypothesis, that an age-associated dampening in the amplitude of rhythmic core clock protein expressions, or alternative ageing associated imbalance between circadian clock proteins, can be linked to age-associated declines in mental performances. Many questions remain: - Will an in depth comparative analyses of hippocampus-based behavior between wildtype and clock gene-deficient mice support the hypothesis? - Is the age-associated decline in clock gene expression hippocampus-specific, or a general phenomenon, and - Does the decline in clock gene expression amplitude or in phase-stability in the peripheral oscillator hippocampus, and/or in the brain circadian master clock residing in the hypothalamic suprachiasmatic nucleus (SCN) matter, with respect to the observed deterioration in mental performance? - Are the observed deficits in habituation in clock gene-deficient mice based on a hippocampal-intrinsic perturbation in time management, or - Is the disrupted temporal gating of hippocampal function related to the lesioned SCN clock in these knockout animals? - Is the observed impairment of long-term memory formation related to deficiencies of memory retrieval into working memory on the second day of habituation testing, rather than to impairments in memory consolidation? A clear answer to these urgent questions requires additional experiments, and demands the generation and investigation of a forebrain-specific conditional clock gene-knockout animal model. Then, the potential role of an clockwork in the brain on mnemonic processes can be refined and attributed to a spatial component. So while the time is ripe to acknowledge the effect of on the time-of-day dependency of cognitive performances, much work remains to support the here hypothesized link between associated decline in circadian behavior and memory formation.

The aging clock: to ‘BMAL'icious toward learning and memory

The aging clock: to ‘BMAL'icious toward learning and memory

Circadian clock proteins control adaptation to novel environment and memory formation

Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated aging phenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-based activities, such as memory formation and the regulation of emotions. Aging is accompanied by the decline in brain physiology, particularly decline in the response and adaptation to novelty. We investigated the role of the circadian clock in exploratory behavior and habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factor BMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- and long-term memory formation. In contrast, mice double-deficient for the circadian proteins CRY1 and CRY2 (repressors of the BMAL1-mediated transcription) demonstrate reduced activity and accelerated habituation when compared to wild type mice. Mice with mutation in theClock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity and impaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatial memory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the proper exploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities through optimization of behavioral learning.

Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA 1 receptor

Lysophosphatidic acid (LPA) is a new, intercellular signalling molecule in the brain that has an important role in adult hippocampal plasticity. Mice lacking the LPA 1 receptor exhibit motor, emotional and cognitive alterations. However, the potential relationship among these concomitant impairments was unclear. Wild-type and maLPA 1-null mice were tested on the hole-board for habituation and spatial learning. MaLPA 1-null mice exhibited reduced exploration in a novel context and a defective intersession habituation that also revealed increased anxiety-like behaviour throughout the hole-board testing. In regard to spatial memory, maLPA 1 nulls failed to reach the controls’ performance at the end of the reference memory task. Moreover, their defective working memory on the first training day suggested a delayed acquisition of the task’s working memory rule, which is also a long term memory component. The temporal interval between trials and the task’s difficulty may explain some of the deficits found in these mice. Principal components analysis revealed that alterations found in each behavioural dimension were independent. Therefore, exploratory and emotional impairments did not account for the cognitive deficits that may be attributed to maLPA 1 nulls’ hippocampal malfunction.

Understanding zebrafish habituation responses to novelty

Though widely used to characterize animal cognitive phenotypes and their modulation, habituation phenotypes have not been extensively investigated in zebrafish (Danio rerio). Utilizing the novel tank test, we examined intra‐ and intersession habituation and demonstrated robust habituation responses in zebrafish. Intrasession habituation analysis determined that selected anxiogenic drugs (caffeine, pentylenetetrazol), as well as stress‐inducing alarm pheromone, attenuated habituation, while the acute anxiolytic agents, morphine and ethanol, had no effect on it. Chronic ethanol and chronic fluoxetine treatment attenuated intrasession habituation in zebrafish. Our study parallels rodent literature on habituation responses to novelty and reconfirms zebrafish as a promising model for cognitive neurobehavioral research. The study was supported by NARSAD, TUNF, TSEF, and TUIRF.

Analyzing habituation responses to novelty in zebrafish ( Danio rerio)

Analysis of habituation is widely used to characterize animal cognitive phenotypes and their modulation. Although zebrafish ( Danio rerio) are increasingly utilized in neurobehavioral research, their habituation responses have not been extensively investigated. Utilizing the novel tank test, we examine intra- and inter-session habituation and demonstrate robust habituation responses in adult zebrafish. Analyzing the intra-session habituation to novelty further, we also show that selected anxiogenic drugs (caffeine, pentylenetetrazole), as well as stress-inducing alarm pheromone, attenuated zebrafish habituation. Some acute anxiolytic agents, such as morphine and ethanol, while predictably reducing zebrafish anxiety, had no effects on habituation. Chronic ethanol and fluoxetine treatments improved intra-session habituation in zebrafish. In general, our study parallels literature on rodent habituation responses to novelty, and reconfirms zebrafish as a promising model for cognitive neurobehavioral research.

Intrasession and intersession habituation in mice: From inbred strain variability to linkage analysis

When placed in a novel environment, mice tend to explore for a period of time, and then reduce the level of exploration. This reduction in locomotor or exploratory behavior is known as habituation and can occur within a single session or across sessions, respectively, termed intrasession and intersession habituation. Recent research indicates that there is a genetic component to habituation behavior and that some of the genes involved differ between the two types of habituation. The genetic evidence also suggests that intrasession habituation and intersession habituation are measuring somewhat different conceptual entities and with more such evidence may eventually help us understand the different pathways involved. Some of the genetic methods and tools used to unravel the roles of specific genes in both types of habituation are outlined here, with examples from the literature, as well as new data, to illustrate that this seemingly simple behavior is actually very complicated in terms of genetics. Evidence to date suggests that a number of genetic regions play roles in one or both types of habituation, and further research will be necessary to determine the specific genes involved.

Lysosomal Enhancement Promotes Synaptic Integrity and Functional Recovery in Mouse Models of Alzheimer's Disease

Reducing protein accumulation is essential for treating Alzheimer's disease (AD) by attenuating a pathogenic cascade that leads to synaptic decline. Z‐Phe‐Ala‐diazomethylketone (PADK) increases lysosomal enzymes 2‐ to 9‐fold in vitro and in vivo. This enhancement clears AD‐related proteins and restores synaptic integrity. Here, PADK produced a dose‐dependent increase in cathepsin D without adverse effects. In the first of two transgenic models of AD, APPSwInd mice of 10–11 months exhibited deficits in coordination and spatial memory. PADK at 23 mg/kg × 9 d recovered open‐field intersession habituation (p<0.03) and improved balance beam and rotarod scores in the mice (p<0.001). 6E10 anti‐Aβ staining also revealed a 39% reduction in hippocampal CA1 sp. In a second model, 18–20‐month old APPswe/PS1dE9 mice exhibited a deficit in episodic spontaneous alternation behavior (SAB). PADK at 20 mg/kg × 10 d improved their SAB to control‐level (p=0.01). Synaptic markers GluR1 and NCAM180 were decreased 23–34% in APPswe/PS1dE9 hippocampus compared to non‐tg mice. Corresponding with the SAB improvement, PADK increased GluR1 and NCAM to non‐tg levels (p=0.0001–0.002). PADK also reduced 6E10 staining of CA1 neurons as well as number and size of plaque structures. Lysosomal modulatory drugs that enhance clearance mechanisms thus have the potential to slow the synaptic decline and cognitive deficits associated with AD.

Behavioral alteration in the adult rats prenatally exposed to para-chlorophenylalanine

In the present work, effects of maternal administration of para-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, on behavior of adult offspring were studied. Pregnant rats were injected intraperitoneally with PCPA (200/100/100/50 mg/kg) either on the gestational days (GD) 8–11 or 14–17, or with vehicle at the same days. Behavioral parameters, in an open field, the Porsolt forced swim test and the Morris water maze test were evaluated at the age of 3–3.5 months in the male and female offspring. The prenatal PCPA increased activity in an open field in the offspring treated on either GD 8–11 or 14–17. The highest levels of the activity were revealed in the male and female offspring treated on GD 14–17. Besides, the PCPA treatment on GD 8–11 or 14–17 facilitated the intersession habituation of activity to repeated exposures to an open field in the male offspring. Both male and female offspring treated on GD 14–17 showed an increased immobility in the Porsolt forced swim test and a significant learning impairment in the Morris water maze. Thus, it has been shown that administration of PCPA to pregnant rats might cause significant changes in the adult offspring behavior. These results provide further evidence that unfavorable influence may have more adverse effects on the behavioral development of rats when exposed during the final trimester of pregnancy than during the second trimester.

Impaired long-term habituation is dissociated from increased locomotor activity after sensorimotor cortex compression

Behavioural habituation to a novel environment is a simple form of learning in rodents. We studied the habituation and locomotor activity (LMA) of Wistar rats subjected to unilateral, transient (30 min) extradural compression (EC) of the right sensorimotor cortex. One group of rats was tested every 24 h during the first 5 days (D1–D5) post-EC. Two other groups were tested for the first time in the LMA boxes on D3 and D6 post-EC and their performance was compared with the group tested on D1 (activity in a novel environment). Total and center locomotion, vertical activity and time spent in the center of the LMA box were reduced on D1 post-EC and normalized by D2. The EC-induced motor paresis was undetectable on the rotarod by D2 and on the beam-walking by D3. Total locomotion, vertical activity and time spent in the center of EC-rats significantly increased from D1 to D3. EC caused neurodegeneration in the cortex, caudate putamen and thalamus as detected by Fluoro–Jade staining. The size of the cortical damage decreased from D2 to D5 in the medial and caudal regions of the compressed hemisphere, in accordance with recovery of motor function. LMA provided additional information in the follow-up of recovery from brain injury and habituation to the environment. Thus, long-term, inter-session habituation was impaired from D1 to D3 but dissociated from increased LMA intra-session on D3, when the motor deficits provoked by EC were already undetectable in the rotarod and beam-walking tests.

Early exploratory behavior abnormalities in R6/1 Huntington's disease transgenic mice

The Huntington's disease (HD) R6/1 transgenic mouse model, containing a human huntington gene exon-1 with approximately 115 CAG repeats, has multiple biochemical and neuroanatomical abnormalities. Overt neurological symptoms have a relatively late onset (15–21 weeks of age). In this paper, we report exploratory behavior abnormalities that appear well before the onset of obvious pathology. The first differences in exploratory behaviors were evident by 4 weeks of age, when R6/1 mice were hyperactive relative to wild-type controls. However, by 6–7 weeks of age, R6/1 mice were less active than controls. R6/1 mice traveled less in the activity monitor, engaged in fewer stereotypic movements, spent more time resting, and traveled less distance per movement than did wild-type controls. R6/1 mice also displayed intersession habituation abnormalities over the 3 days of testing. These behavioral abnormalities precede the earliest neurochemical and molecular changes reported in the literature to date, and thus indicate subtle early pathology that has not yet been documented. These behavioral abnormalities also occur prior to weight loss in the transgenic mice. Since we were able to detect an abnormal phenotype at an early age in R6/1 mice, this assay may be a useful tool for evaluating therapeutic agents.

A Region on Chromosome 15 Controls Intersession Habituation in Mice

Habituation to a novel environment, as measured by a change in exploratory activity over time, can be measured both within (intrasession) and across (intersession) sessions. The role of genetics in intrasession habituation has been investigated previously in quantitative trait loci studies, but little attention has been focused on the role of genetics on intersession habituation. We reported recently that inbred strains respond differently in an intersession habituation test. By testing a total of 25 BXD recombinant inbred lines, we were able to map a chromosomal region that strongly influences the way in which mice habituate. This region located on chromosome 15 appears to the major one affecting habituation and accounts for 80% of the genetic variance. We subsequently confirmed this map position by testing (C57BL/6J x DBA/2J) F2 mice.

Habituation of activity in an open field: A survey of inbred strains and F1 hybrids.

To determine if there is genetic variability in habituation of activity in an open field, we examined a number of inbred strains and F1 hybrids. Using 5-min exposures to a dark open field, we measured changes in exploratory behavior over 3 consecutive days in 129S3/SvImJ, A/J, BALB/ cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, FVB/NJ, (B6 x 129)F1/J, and (B6 x C3H) F1/J male and female mice. Strain differences in open-field activity and in habituation were evident. Some of the strain differences were further modified by sex. The strains and F1's could be separated into groups that increased, decreased, or did not modify their activities across testing sessions. In a second study, the effects of altering the floor surface on habituation were examined in male 129S3/SvImJ, C57BL/6J, DBA/2J, and (B6 x 129)F1/J mice. When the floor was altered after 3 consecutive days of habituation, increased activity levels were evident. There were strain differences in the responsiveness to the changes in the floor. These results confirm a genetic role in intersession habituation to an open field.

Head-dipping in rats with superior collicular, medial frontal cortical and hippocampal lesions

When tested in a modified “holeboard” apparatus, hooded rats with deep superior collicular lesions were hyperactive, reared less than controls and spent a great deal of time at the apparatus perimeter. They failed to explore holes in the floor and frequently fell into them. Those with lesions restricted to superficial laminae showed reduced rearing, and preference for the perimeter but were normally active and explored floor holes as frequently as controls. The frontal cortical group failed to differ from controls on any measure. Hippocampals exhibited reduced intersession habituation of locomotor activity. It was concluded that superior colliculus, hippocampus and medial frontal cortex have separate functional roles. Differences between deep and superficial collicular lesions effects might arise because deep lesions disrupt both motor integration and attention while superficial lesions disrupt only the latter. Alternatively, since superficial lesions spare lateral tissue subserving attention to stimuli in lower portions of the visual field, they may produce a less global attentional deficiency which has less impact upon motor function.

Effects of differential interference with postnatal cerebellar neurogenesis on motor performance, activity level, and maze learning of rats: a developmental study.

The region of the cerebellum was X-irradiated in infant rats with selected exposure schedules designed to produce animals in which the cerebellar cortex was (a) essentially normal except for agenesis of late forming granule cells with axons situated in the uppermost molecular layer (12--15X), (b) lacking in stellate cells, with a severe reduction in granule cells with axons in the upper molecular layer (8--15X), (c) morphologically disorganized but had only intermediate cell agenesis (4--5X), or (d) disorganized and devoid of practically all postnatally forming interneurons (4--15X). In the first two experiments young adults had to traverse rotating rods that differed in texture and types of obstacles. The 8--15X animals showed no deficits on any of the rods tested. The third study dealt with spontaneous motor performance in the open field at three ages. The 4--5X and 4--15X animals were hypoactive as infants and young adults; this was attributed to their motor deficits. The 8--15X and 12--15X animals were hyperactive in the open field as young adults. The fourth experiment examined intra- and/or intersession habituation. No group differences were found in habituation patterns. In the fifth experiment, using activity wheels, the 4--15X group was hypoactive, and the 8--15X and 12--15X groups were hyperactive as young adults. In the sixth experiment young adults were tested for learning performance in a multiple-unit water maze. The 4--15X group was deficient on single alternation; the 4--5X and 12--15X groups on double alternation. The seventh experiment shed some light on the single alternation deficit of the 4--15X group; only these animals failed to alternate spontaneously in a nonaversive situation. In conclusion, these behavioral results, combined with those of recent morphological investigations, suggest that the cerebellar cortex is hierarchically organized: The basal domain of Purkinje cells and the lower molecular layer are implicated in the coordination of movements; the apical domain of Purkinje cells and the upper molecular layer, in the coordination of actions.