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9.19J | Spring 2001 | Undergraduate

# Cognitive & Behavioral Genetics

The readings listed below are the foundation of this course. Where available, journal article abstracts from PubMed (an online database providing access to citations from biomedical literature) are included.

### Lecture #1

Pinker, S. “The Blank Slate, the Noble Savage, and the Ghost in the Machine.” In The Tanner Lectures on Human Values 21. Edited by G. B. Peterson. Salt Lake City: University of Utah Press, 2000.

Ridley, M. “Chromosome 21: Eugenics.” In Genome. New York: Harper Collins, 1999.

Turkheimer, E. “Three Laws of Behavioral Genetics and What They Mean.” In Current Directions in Psychological Science, 9. 2000, 160-164.

Hyman, S. E. “Introduction to the Complex Genetics of Mental Disorders.” In Biological Psychiatry, 45. 1999, 518-521.

Plomin, R. “Psychology in a Post-genomics World: It will be More Important than Ever.” American Psychological Society Observer, 13. 2000.

Lykken, D. T., A. McGue, A. Tellegen, and T. J. Bouchard Jr. “Emergenesis: Genetic Traits that May Not Run in Families.” American Psychology, 1992.

> PubMed abstract: Traits that are influenced by a configuration–rather than by a simple sum–of polymorphic genes may not be seen to be genetic unless one studies monozygotic twins (who share all their genes and thus all gene configurations) because such “emergenic” traits will tend not to run in families. Personal idiosyncrasies that have been found to be surprisingly concordant among MZ twins separated in infancy and reared apart may be emergenic traits. More speculatively, important human traits like leadership, genius in its many manifestations, being an effective therapist or parent, as well as certain psychopathological syndromes may also be emergenic. These ideas reemphasize the importance of the role played in human affairs by genetic variation.

### Lecture #4

Gogos, J. A., et al. “The Gene Encoding Proline Dehydrogenase Modulates Sensorimotor Gating in Mice.” In Nature Genetics. 21, 1999, 434-439.

> PubMed abstract: Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.

Anagnostaras, S. G., M. G. Craske, and M. S. Fanselow. “Anxiety: At the Intersection of Genes and Experience.” In Nature Neuroscience. 2, 1999, 780-782.

> PubMed abstract: Human anxiety disorders arise from a combination of genetic vulnerability and traumatic experience. Mice with a GABAA receptor mutation may provide a model for these disorders.

Crestani, F., et al. “Decreased GABAA- Receptor Clustering Results in Enhanced Anxiety and a Bias for Threat Cues.” In Nature Neuroscience. 2, 1999, 833-839.

> PubMed abstract: Patients with panic disorders show a deficit of GABAA receptors in the hippocampus, parahippocampus and orbitofrontal cortex. Synaptic clustering of GABAA receptors in mice heterozygous for the gamma2 subunit was reduced, mainly in hippocampus and cerebral cortex. The gamma2 +/- mice showed enhanced behavioral inhibition toward natural aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination learning. Implicit and spatial memory as well as long-term potentiation in hippocampus were unchanged. Thus gamma2 +/- mice represent a model of anxiety characterized by harm avoidance behavior and an explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations. This model implicates GABAA-receptor dysfunction in patients as a causal predisposition to anxiety disorders.

Tecott, L. H. “Designer Genes and Anti - Anxiety Drugs.” In Nature Neuroscience. 2000, 529-530.

McKernan, R. M., et al. “Sedative But Not Anxiolytic Properties of Benzodiazepines are Mediated by the GABAA Receptor a1 Subtype.” In Nature Neuroscience. 3, 2000, 587-592.

> PubMed abstract: Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

### Lecture #6

Helmuth, L. “Early Insult Rewires Pain Circuits.” In Science 289. 2000, 521-522. Netscape

Ruda, M. A., Q. D. Ling, A. G. Hohmann, Y. B. Peng, and T. Tachibana. “Altered Nociceptive Neuronal Circuits After Neonatal Peripheral Inflammation.” In Science 289. 2000, 628-630.

> PubMed abstract: Nociceptive neuronal circuits are formed during embryonic and postnatal times when painful stimuli are normally absent or limited. Today, medical procedures for neonates with health risks can involve tissue injury and pain for which the long-term effects are unknown. To investigate the impact of neonatal tissue injury and pain on development of nociceptive neuronal circuitry, we used an animal model of persistent hind paw peripheral inflammation. We found that, as adults, these animals exhibited spinal neuronal circuits with increased input and segmental changes in nociceptive primary afferent axons and altered responses to sensory stimulation.

### Lecture #7

Selection of papers from recent special issue of Journal of Cognitive Neuroscience by Ursula Bellugi and colleagues.

Frangiskakis, J. M., A. K. Ewart, A. C. Morris, C. B. Mervis, J. Bertrand, B. F. Robinson, B. P. Klein, G. J. Ensing, L. A. Everett, E. D. Green, C. Proschel, N. J. Gutowski, M. Noble, D. L. Atkinson, S. J. Odelberg, and M. T. Keating. “LIM-Kinase1 Hemizygosity Implicated in Impaired Visuospatial Constructive Cognition.” In Cell 86. 1996, 59-69.

> PubMed abstract: To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

Rosenblatt, J., and T. J. Mitchison. “Actin, Cofilin, and Cognition.” In Nature, 393. 1998, 739 -740.

Paterson, S. J., J. H. Brown, M. K. Gsodl, M. H. Johnson, and A. Karmiloff-Smith. “Cognitive Modularity and Genetic Disorders.” In Science 286. 1999, 2355-2358.

> PubMed abstract: This study challenges the use of adult neuropsychological models for explaining developmental disorders of genetic origin. When uneven cognitive profiles are found in childhood or adulthood, it is assumed that such phenotypic outcomes characterize infant starting states, and it has been claimed that modules subserving these abilities start out either intact or impaired. Findings from two experiments with infants with Williams syndrome (a phenotype selected to bolster innate modularity claims) indicate a within-syndrome double dissociation: For numerosity judgments, they do well in infancy but poorly in adulthood, whereas for language, they perform poorly in infancy but well in adulthood. The theoretical and clinical implications of these results could lead to a shift in focus for studies of genetic disorders.

Bishop, D. “Enhanced: An Innate Basis for Language?” In Science 286. 1999, 2283-2284. Netscape

### Lecture #8

Stromswold, K. “The Heritability of Language: A Review and Meta-analysis of Twin and Adoption Studies.” In Language. Press
van der Lely, H. K. J., S. Rosen, and A. McClelland. “Evidence for a Grammar-specific Deficit in Children.” In Current Biology. 8, 1998, 1253-1258.

> PubMed abstract: Specific language impairment (SLI) is a disorder in which language acquisition is impaired in an otherwise normally developing child. SLI affects around 7% of children. The existence of a purely grammatical form of SLI has become extremely controversial because it points to the existence and innateness of a putative grammatical subsystem in the brain. Some researchers dispute the existence of a purely grammatical form of SLI. They hypothesise that SLI in children is caused by deficits in auditory and/or general cognitive processing, or social factors. There are also claims that the cognitive abilities of people with SLI have not yet been sufficiently characterised to substantiate the existence of SLI in a pure grammatical form. RESULTS: We present a case study of a boy, known as AZ, with SLI. To investigate the claim for a primary grammatical impairment, we distinguish between grammatical abilities, non-grammatical language abilities and non-verbal cognitive abilities. We investigated AZ’s abilities in each of these areas. AZ performed normally on auditory and cognitive tasks, yet exhibited severe grammatical impairments. This is evidence for a developmental grammatical deficit that cannot be explained as a by-product of retardation or auditory difficulties. CONCLUSIONS: The case of AZ provides evidence supporting the existence of a genetically determined, specialised mechanism that is necessary for the normal development of human language.

Fisher, S. E., F. Vargha-Khadem, K. E. Watkins, A. P. Monaco, and M. E. Pembrey. “Localization of a Gene Implicated in a Severe Speech and Language Disorder.” In Nature Genetics. 18, 1998, 168-170.

> PubMed abstract: Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.

### Lecture #10

Lewis, D. A., and J. A. Lieberman. “Catching Up on Schizophrenia: Natural History and Neurobiology.” In Neuron 28. 2000, 325-334.

> PubMed abstract: Schizophrenia is a complex disorder, and there is substantial evidence supporting a genetic etiology. Despite this, prior attempts to localize susceptibility loci have produced predominantly suggestive findings. A genome-wide scan for schizophrenia susceptibility loci in 22 extended families with high rates of schizophrenia provided highly significant evidence of linkage to chromosome 1 (1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage (lod) score of 6.50. This linkage result should provide sufficient power to allow the positional cloning of the underlying susceptibility gene.

Brzustowicz, L. M., K. A. Hodgkinson, E. W. C. Chow, W. G. Honer, and A. S. Bassett. “Location of a Major Susceptibility Locus for Familial Schizophrenia on Chromosome 1q21-q22.” In Science 288. 678-682.

## Course Info

##### Instructors

- Prof. Elly Nedivi
- Prof. Steven Pinker

##### Departments

- Brain and Cognitive Sciences
- Biology

##### As Taught In

Spring 2001

##### Level

Undergraduate

##### Topics

- Science
  - Biology
    - Genetics
    - Neuroscience
  - Cognitive Science
- Social Science
  - Psychology

##### Learning Resource Types

assignment Written Assignments

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