A relationship between cerebellar Purkinje cells and spatial working memory demonstrated in a lurcher/chimera mouse model system

New emphasis has been placed upon cerebellar research because of recent reports demonstrating involvement of the cerebellum in non‐motor cognitive behaviors. Included in the growing list of cognitive functions associated with cerebellar activation is working memory. In this study, we explore the potential role of the cerebellum in spatial working memory using a mouse model of Purkinje cell loss. Specifically, we make aggregation chimeras between heterozygous lurcher (Lc/+) mutant embryos and +/+ (wildtype) embryos and tested them in the delayed matching‐to‐position (DMTP) task. Lc/+ mice lose 100% of their Purkinje cells postnatally due to a cell‐intrinsic gain‐of‐function mutation. Lc/+<−>+/+ chimeras therefore have Purkinje cells ranging from 0 to normal numbers. Through histological examination of chimeric mice and observations of motor ability, we showed that ataxia is dependent upon both the number and distribution of Purkinje cells in the cerebellum. In addition, we found that Lc/+ mice, with a complete loss of Purkinje cells, have a generalized deficit in DMTP performance that is probably associated with their motor impairment. Finally, we found that Lc/+<−>+/+ chimeric mice, as a group, did not differ from control mice in this task. Rather, surprisingly, analysis of their total Purkinje cells and performance in the DMTP task revealed a significant negative relationship between these two variables. Together, these findings indicate that the cerebellum plays a minor or indirect role in spatial working memory.

[1]  G. Mittleman,et al.  The cerebellum and spatial ability: dissection of motor and cognitive components with a mouse model system , 2003, The European journal of neuroscience.

[2]  Robert L. Mason,et al.  Statistical Principles in Experimental Design , 2003 .

[3]  David M. Murray,et al.  Methods To Reduce The Impact Of Intraclass Correlation In Group-Randomized Trials , 2003, Evaluation review.

[4]  C. C. Wrenn,et al.  Lack of effect of moderate Purkinje cell loss on working memory , 2001, Neuroscience.

[5]  T. Steckler,et al.  Effects of cholinergic manipulation on operant delayed non-matching to position performance in two inbred strains of mice , 2001, Behavioural Brain Research.

[6]  J A Fiez,et al.  Bridging the Gap Between Neuroimaging and Neuropsychology: Using Working Memory as a Case-Study , 2001, Journal of clinical and experimental neuropsychology.

[7]  R. Passingham,et al.  The cerebellum and cognition: cerebellar lesions do not impair spatial working memory or visual associative learning in monkeys , 1999, The European journal of neuroscience.

[8]  M. Molinari,et al.  Verbal short-term store-rehearsal system and the cerebellum. Evidence from a patient with a right cerebellar lesion. , 1998, Brain : a journal of neurology.

[9]  J. Desmond,et al.  Neuroimaging studies of the cerebellum: language, learning and memory , 1998, Trends in Cognitive Sciences.

[10]  T. Kemper,et al.  Neuropathology of infantile autism , 1998, Molecular Psychiatry.

[11]  A. Bailey,et al.  A clinicopathological study of autism. , 1998, Brain : a journal of neurology.

[12]  Kimitaka Kaga,et al.  Mechanism of short-term memory and repetition in conduction aphasia and related cognitive disorders: a neuropsychological, audiological and neuroimaging study , 1998, Journal of the Neurological Sciences.

[13]  H. Damasio,et al.  Dissociation Of Working Memory from Decision Making within the Human Prefrontal Cortex , 1998, The Journal of Neuroscience.

[14]  R W Guillery,et al.  Quantification without pontification: Choosing a method for counting objects in sectioned tissues , 1997, The Journal of comparative neurology.

[15]  D. Linden,et al.  Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene , 1997, Nature.

[16]  N. Dronkers.  A new brain region for coordinating speech articulation , 1996, Nature.

[17]  P. Roland,et al.  Activation of Multi‐modal Cortical Areas Underlies Short‐term Memory , 1996, The European journal of neuroscience.

[18]  S E Petersen,et al.  A positron emission tomography study of the short-term maintenance of verbal information , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  J. B. Demb,et al.  Functional MRI measurement of language lateralization in Wada-tested patients. , 1995, Brain : a journal of neurology.

[20]  J Jonides,et al.  Human Rehearsal Processes and the Frontal Lobes: PET Evidence , 1995, Annals of the New York Academy of Sciences.

[21]  A. Ardila.  Luria's approach to neuropsychological assessment. , 1992, The International journal of neuroscience.

[22]  Douglas Wahlsten,et al.  Techniques for the Genetic Analysis of Brain and Behavior: Focus on the Mouse , 1992 .

[23]  S. Iversen,et al.  Proactive interference effects on short-term memory in rats: II. Effects in young and aged rats. , 1990, Behavioral neuroscience.

[24]  S B Dunnett,et al.  Proactive interference effects on short-term memory in rats: I. Basic parameters and drug effects. , 1990, Behavioral neuroscience.

[25]  A. Scheibel,et al.  Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report. , 1986, The American journal of psychiatry.

[26]  T. Kemper,et al.  Histoanatomic observations of the brain in early infantile autism , 1985, Neurology.

[27]  A. Damasio,et al.  The anatomic basis of pure alexia , 1983, Neurology.

[28]  K. Herrup,et al.  Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimaeric mice. I. Qualitative studies. , 1982, Journal of embryology and experimental morphology.

[29]  K. Caddy,et al.  Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. , 1979, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[30]  F. Gage,et al.  Hippocampal connections and spatial discrimination , 1978, Brain Research.

[31]  R. J. Mullen,et al.  Relationship of genotype and degree of chimerism in coat color to sex ratios and gametogenesis in chimeric mice. , 1971, The Journal of experimental zoology.

[32]  M. Abercrombie.  Estimation of nuclear population from microtome sections , 1946, The Anatomical record.

[33]  A. Sahgal.  Contrasting effects of vasopressin, desglycinamide-vasopressin and amphetamine on a delayed matching to position task in rats , 2004, Psychopharmacology.

[34]  A. Sahgal.  Some limitations of indices derived from signal detection theory: evaluation of an alternative index for measuring bias in memory tasks , 2004, Psychopharmacology.

[35]  S. Dunnett.  Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats , 2004, Psychopharmacology.

[36]  S. Iversen,et al.  Delay-dependent short-term memory deficits in aged rats , 2004, Psychopharmacology.

[37]  J. Schmahmann,et al.  Rediscovery of an early concept. , 1997, International review of neurobiology.

[38]  M. Raichle,et al.  Linguistic processing. , 1997, International review of neurobiology.

[39]  Leslie G. Ungerleider,et al.  Object and spatial visual working memory activate separate neural systems in human cortex. , 1996, Cerebral cortex.

[40]  Dunnett Sb.  The role and repair of forebrain cholinergic systems in short-term memory. Studies using the delayed matching-to-position task in rats. , 1993 .

[41]  S. Dunnett.  The role and repair of forebrain cholinergic systems in short-term memory. Studies using the delayed matching-to-position task in rats. , 1993, Advances in neurology.

[42]  R. Wetts,et al.  Mouse chimeras in the study of genetic and structural determinants of behavior , 1992 .

[43]  D. Howes,et al.  The Nature of Conduction Aphasia: A Study of Anatomic and Clinical Features and of Underlying Mechanisms , 1977 .