action, reaction, response = behavior
clear-cut cases of genetic influences--known since early 1900s
field of psychology...
            whole paradigm--Behaviorism (Watsonians and Skinnerians)
                          "i do not know what makes an animal hungry and i do not care"
nature-nuture...when it was still a controversy
1950s--acceptance of interaction:
        "all behavior patterns are influenced both genetically and environmentally"
emergence of Behavior-Genetics...
            development of approaches....

1.    Behavior Differences in related organisms--evidence for genetic influence

    - comparative approach:    behavior differences in genetic strains of species
            rationale:    if closely related organisms exist in similar enviornments and their survival needs are identical, then any observed behavioral differences may be due to genotypic differences

(A) Alcohol Preference in Mice
        - preference or aversion to ethanol in different strains
e.g. consumption of 4 strains over 3 weeks
            each strain--7 options for their "drinking pleasure" (pure H20, 2.5-15.0% range)
        some show preference, others aversion      (Table 24.1)
        - raised over many generations in same environment
        - therefore: genotypic differences = differences in alcohol preference
        "presumably these strains vary only by the fixation of different alleles at particular loci"
but: underlying mechanism unclear!
suggested: differences in primary enzymes of alcohol metabolism (e.g. ADH and AHD) may result in these behavioral differences
to date: no correlation between alcohol preference or metabolism and these biochemical markers has been established (need for incorporation of other markers)

(B) Open-Field Behavior in Mice
        -study exploratory and emotional behavior
        - new enviro = defecation and urination
            in lab: grid floor enclosed box (record movements)
                            emotion (record sh*ts)
        - different inbred strains = different open-field responses
DeFries et al. - 2 strains:
                - BALB/cJ (albino)    low exploration; very emotional
                - C57BL/6j (normal)    high exploration; low emotional
test: cross 2 strains then interbred several generations
        F2....Fn - cc, Cc, CC rats tested in open-field
in all cases:        - pigmented mice = behr of C57
                            - albino mice = behr of BALB
**conclusion: c allele behaves pleiotropically (coat color, behr)
    heritability analysis (h2)...
                this locus accounts for 12% of the variance in open-field activity
                this locus accounts for 26% of the variance in sh*t-related emotion
therefore support for polygenically controlled (i.e. other loci involved)

2.    Modified Behavior may be artificially selected from heterogenous populations

    -approach -organisms are artificially selected from a genetically heterogeneous population that contains members that exhibit a behavioral trait.
    rationale -if genetic strains can be established, where this behavior is uniformly expressed, this trait can be transferred by genetic crosses to another strain that initially does not exhibit the behavior under study, the positive influence of the genotype is established.

(A) Maze learning in rats
Tolman 1924
82 white rats (heterozygous ancestry)
            measured ability "to learn" to obtain food (multiple T maze)
            over trials errors decrease, eventually no errors (hungry rats)
            from 82 selected:  9 pairs-"brightest" and "dullest" (two lines)
            selection continued over generations...
other similar studies (Tryon, 1942 - 18 selected generations   Fig 24.2 )
*Cannot generalize studies to all intelligence (IQ tests...)

(B) Geotaxis in Drosphila
Hirsch et al.
    mass screening device
    flies added to vertical maze
    select for positive and negative geotaxis (selection:  30 yrs, 500 gen's, 80,000 flies)
Conclusion:  geotaxis under polygenic control (i.e. more than one loci involved)

on chromosomes 2,3 and X... Fig 24.5
        negatively geotaxis flies:  gradient = 2>3>X
        positively geotaxis flies:  gradient = X>3>2
Conclusion:  geotaxis is under polygenic control and the loci involved are located on all 3 chromosomes

3. The effect of single genes that affect behavior can be studied.

Genetic crosses - established inheritance patterns
many cases - no simple Mendelian pattern
third approach:  Isolate and study the effects of single genes of behr
        - mutation in a single gene may alter that behr
    first step:  defining a gene-controlling behr (then isolation, cloning, molecular characterization)

(A) Nest cleaning in bees
    nest infected with bacillus larvae
    hygienic behr of worker bees
Rothenbuhler (1964) - hygenic (brown) X nonhygenic (VanScoy) Fig 24.6
Conclusion:  either a gene complex or two independently assorting alleles (u and r) are responsible for hygienic behr.

(B) Molecular motors in bacteria
     E.coli and Salmonella - move along chemical gradients; flagellar action controls (runs and tumbles)
     Chemical attractant - runs up the gradient extended (chemical repellant - vice versa) Fig 24.9
     E. coli - membrane spanning receptors, sense chemicals, initiate intracellular responses
*These receptor proteins equal products of gene family called transducers* Fig 24.10
        Cytoplasmic surface of chemoreceptor protein + CheA/CheW = complex
            - CheA and chemoreceptor - direct interaction
            - CheW - enhances the association
            - CheA mutants are non-chemotactic
What happens...
    phosphorylation, molecular switch, dephosphorylation
    presence of attractant - cycle reversed
Results suggests:  signal transduction is not initiated by the formation of the complex, but rather through conformational changes in the complex brought about by sensory molecules

(C) Locomotor behr in mice
Waltzer mutation in mice ("I call it the nellie")
Crosses (mutant X normal) - simple recessive pattern (monohybrid mating)
    this eg:  mutation - structural anomaly - alters behr

4. C. elegans and the study of behavior genetics.

Sydney Brenner- study the relationship between behr and the nervous system in c. elegans
Why c. elegans? - simplicity (959 somatic cells)
three classes of behr was studied:
            i.    chemotaxis - many mutations have been isolated but only 3 are characterized (+vely chemotactic for cAMP and GMP, anions and cations)
            ii.    thermotaxis - cryophilic mutants move towards cooler temperatures and thermophilic mutants move toward warmer temperatures (no relation with nervous system)
            iii.    generalized movements - of 300 induced mutations, 77 affect movement
                                        - wild type: smooth sinuous pattern
                                        - unc mutant: uncoordinated
                                        - rol mutant: "rollers"
wrt feeding behr...
            pharynx contains 60 cells, 20 are neurons (only 1 essential for life)
            pharyngeal nervous system consists of 1 pair of nerves connecting it to the rest of the nervous system
Avery - isolate and charecterize the genes that control feeding behr
    found: 52 mutations were assigned to 35 genes, dispersed on all 6 chromosomes and it's estimated that 60 genes are involved
three categories of mutants:    i. eat mutants - affect fxn of pharyngeal muscles
                                         ii. pha mutants - abnormal pharynx
                                         iii. phm mutants - weak and irregular pharyngeal muscle contraction

5. Drosophila and its unique approach to the study of behavioral genetics.

Sturtevant (1915) - observed that x-linked recessive gene ("yellow") affects mating preference in females
Bastock (1956) - observed that the "yellow" mutation alters the pattern of male courtship making these males less successful at mating.

(A) Mosaic Flies
    Phototaxis - normal flies are +vely phototactic, mutations are induced in males with EMS and mated with attached-x virgin females; all male progeny exhibiting abnormal behr were isolated
                            3 mutants were identified:
                            i. runner mutants - move quickly to and from light
                            ii. -ve phototactic mutants - move away from light
                            iii. nonphototactic mutants - show no preference
Conclusion: x-linked recessive mutation Fig 24.13

Where within the fly must gene expression occur to produce normal phototaxis (+ve)?
        mosaic: some tissues are mutant, some tissues are wild type
            (used to find primary focus of abnormal behr)
To produce mosaic flies... Fig 24.14
        *when and where the ring-x is lost in development determines the pattern of mosaicism  Fig 24.15
Conclusion:
The focus of the abnormal behr was found to be the eye itself (normal body, mutant eyes = abnormal behr; one mutant eye, one normal eye = unusual behr)

A large number of genes affecting behr in Drosophila have been identified and analyzed (see Table 24.4).

(B) Neurogenetics ( Fig 24.16 )
Two classes of mutants were identified:
    i. paralytic - temperature sensitve allele (defect in Na trasnport associated with conduction in nerve impulses)
    ii. shaker - defect in K transport

Cloned Drosophila genes have been used as probes to isolate human ion channel genes (e.g. cardiac arrythymia)

(C) Learning in Drosophila
            Classical Conditioning (pairing of odor and shock; CS-US...)
            Selecting Mutants - mating mutagenized wild type males and normal wild females yield learning mutants (e.g. amnesia mutants)
            All mutants so far are x-linked.
            Linkage between cAMP and learning (e.g. rutabaga)

6. Behavior Genetics in Humans.

Two problems: i. hard to define
                         ii. environmental factors

        "human behavior has thus become a happy hunting ground for literary amateurs. And the reason is that psychology and genetics whose business it is to explain behavior have failed to face the task together."

Genetic Disorders caused by single genes:
i. Huntington's Disease - affects the nervous system, resulting in gradual loss of motor fxn and coordination
ii. MAOA - mental retardation and aggressive behr ( Fig 24.17 )
iii. Lesch-Nyhan Syndrome - mental and developmental retardation and uncontrolled self-mutilation
iv. Tay-Sachs Disease - severe mental retardation
v. PKU - unless treated results in mental deficits

Multifactorial Traits: (G-E)
i. Manic Depression
ii. Schizophrenia
iii. Alcoholism...

- addictions like alcoholism are multifactorial disorders
- twin studies have established that the role of genetic variation is profound, however twins with the same genotype often do not share the same behavior (gene-environment interaction)
- features of addiction: 1. compulsive drug seeking
                                     2. use despite negative consequences
- genetic variation has been related to the severity of addiction
- the severity of additive symptoms is correlated with an increased likelihood of multiple drug use
- alcoholism is the most prevalent addiction across cultures and generations

Comorbidity of Addictive Disorders

Addictive disorders are closely associated with:
    1. other substance dependencies (e.g. more than 80% of alcoholics smoke cigarettes)
    2. other psychiatric disorders (e.g. severe alcoholism and suicidality and impulsivity tend to co-exist)

Common and Distinct Neurobiologic Effects of Addiction to Alcohol

- Addictive substances affect many of the neurotransmitter systems in the brain
- One pathway, the mesolimbic dopamine system, seems to be vital to the action of all addictive substances
    (suggested brain reward mechanism)
- This pathway is associated with feeling pleasure; psychostimulant such as alcohol exert a primary reinforcing effect by inducing the release of dopamine
- Continued reinforcement is mediated by the psychostimulants which block the binding of dopamine (DA antagonists) to its transporter and by interacting with many dopamine receptors, including D1, D2, and D3
note: ethanol has an effect on a variety of targets within the cell membrane (e.g. neurotransmitter membrane receptors, ion channels and neurotransmitter release)

The Heritability of Addictive Disorders

- Addictive diseases, such as alcoholism are familial. Therefore a family history of alcoholism would indicate a strong risk factor for the development of alcoholism for someone in that family.
- Twin studies and adoption studies demonstrate that genetic factors are useful for determining vulnerability especially to more severe forms of alcoholism.
- The heritability of alcoholism was observed to be 0.38 in one meta-analysis.
Note: the genetic component of severe early-onset alcoholism appears to be a great deal more than that of late-onset alcoholism.

Genetic Heterogeneity

It is possible that genetic characteristics may be shared by addicted individuals, but individual differences indicate that there are other influences/factors for addictions.

For alcoholism, variation exists in...
1.    Prevalence - high vs. low in certain groups (e.g. low in Muslim and Mormon groups)
2.    Presentation - from long-term, heavy, daily drinking to episodes of heavy drinking
3.    Severity - amount of dependence (psychological vs. physical)
4.    Sequelae - behavioral and psychiatric - physical
5.    Associated disorders - MD, bulimia, etc.

Because of the complexity of its causation, it is speculated that the genetic factors within individuals will also vary. (i.e. addictions are under the control of many genes on several chromosomes)
Moreover, the phenotypic expression of addiction is largely due to environmental interactions.

Determining the Genetic Basis of Addictions

*large samples are needed in order to determine the smallest genetic effects*

4 Methods:
1. Linkage analysis - inheritance pattern from pedigrees
2. Allele sharing methods - comparison of affected relatives to detect excess genotype sharing
3. Association studies - comparison of unrelated affected and unaffected individuals
4. Analysis of inbred, transgenic, and gene-knockout animals (mice and rats)
        - mapping of quantitative trait loci (determined by multiple genes responsible for the addiction)

Genetic Studies of Addictive Disorders in Humans

Clinical Subgroups:
    Alcoholics are classified into more homogeneous groups by the factors that distinguish variations.

Electrophysiologic Markers:
    e.g. low resting brain activity is 3x more common in alcoholics than non-alcoholics

Alcohol Sensitivity:
    e.g. lower hormonal response to modest dose of alcohol predicted a fourfold increase in the risk for future alcoholism in young men independent of family history.

Neurochemical Markers:
    e.g. studies show that low platelet MAOB activity might be a marker for alcoholism (particularly early onset, severe alcoholism in men)
    e.g. several case studies have found lower adenylate cyclase activity in the platelets and lymphocytes of alcoholics and in the brains of postmortem alcoholics

Protective Genes:
    The only genes for alcoholism identified are "protective" (e.g. ADH2, ALDH1, ALDH2)
Upon the ingestion of alcohol, causes the unpleasant effects (hangover etc.). This is accomplished by decreasing the rate of metabolism of acetaldehyde, thus increasing levels of acetaldehyde in the body. This is a toxic component, hence the unpleasant effects.
    Therefore, these genes are an inborn model of protection from alcoholism.

Whole-Genome Linkage Scans:
    Two studies have identified linkage of alcoholism to chromosome regions:
1. Southwestern Native American population:
    - chr. 11p. (near the DRD4 dopamine receptor and tyrosine hydroxylase genes)
    - chr. 4p. (near a GABAa receptor gene cluster)
2. Evidence for linakge to chromsomes 1 and 7

*both studies found a little evidence for on chr. 4q at the location of the alcohol dehydrogenase gene cluster.

These are just the basics of this field. Many studies, taking advantage of techniques like PCR that we have already discussed in this course, have been carried out of late. For a more detailed look at them and their respective findings please stay tuned...