introduction to neuroscience: behavioral neuroscience · 2013-09-11 · 1. deficits in...
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Behavioral Neuroscience Introduction to Neuroscience:
Lecture 4
Tali Kimchi Department of Neurobiology [email protected]
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Sexual Dimorphism in Brain and Behavior-part II
Studying Social-related Mental Disorders using Animal Models
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♂ ♀ XY
XX
Estradiol &
Progesterone
Testosterone &
Estradiol Organization
Dimorphism of the brain: differentiation and activation
-
Bipotential gonad
SRY gene
+
Ovary Testis
Estradiol &
Progesterone
Sex-specific behaviors
Activation Testosterone &
Estradiol
Organization
(permanent changes)
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Sexual dimorphism can NOT be explained just by sex hormones organization affects X
Y
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De Vries et al 2002 J Neuroscience
Nu
mb
er
of T
H c
ell
Evidence for the affect of Y-linked genes on sexual dimorphism of the brain
♂ ♀
♂ ♀
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Definition: A gene or chromosome region that is expressed when inherited from one (maternal or paternal) parent. But not when inherited from the other parent (i.e. parent-specific inactivation of a gene).
Imprinting genes
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Mechanism:
•Imprinting is determined by allele-specific DNA methylation at critical sites (e.g. promoter region) which represses the expression of the gene.
Imprinting genes
•DNA methylation is the convalent attachment of methyl to the cytosine using DNA methylase enzyme.
Result: DNA methalation may inhibit transcription by mainly preventing the binding of transcription factors to the promoter region.
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Biology function: “The battle of the sexes theory” or “parental conflict theory” •The father is more “interested” in the growth of the offspring, at the expense of the mother. •The mother’s interests is to conserve resources for her survival and provide sufficient nutrition to her pups.
Imprinting genes
•Parental genes are selected to extract resources from the mother to give to the fetus, while maternal imprinting genes are selected to inhibit this transfer of resources.
Maternal imprinting genes will repress growth of pups and paternal imprinting genes will enhance growth.
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Peg1 mutant female will exhibit deficiency in maternal behaviors
Curley et al 2004 Proc R Soc B
Paternally expressed genes (Peg1/Mest)
Normal animal Peg1 enhance maternal care
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Lefebvre et al 1998; Nature Genetics Keverne et al 1999; Science
Latency of nest building
Time to retrieve pups
Mutant
Wild type
Virgin ♀ Postparum ♀
Virgin ♀ Postparum ♀
Paternally expressed genes (Peg3)
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♂ ♀
Hormones Hormones
Organization Activation
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The Medial Preoptic Area (MPOA) is activated by testosterone and is essential to the activation of male sexual behavior
Castration Microinjection of testosterone into the MPOA
Reinstate sexual behavior
Abolish of sexual behavior
MPOA lesion Abolish of sexual behavior
♂ ♀
Anderogen Receptor expression in the MPOA
Intact male Sexual behavior Increase neuronal firing rate in the MPOA
Sex-specific pheromone stimuli or mating behavior
Induce c-fos in MPOA of both males and females (c-fos is immediate early gene, indirect molecular marker of neuronal activity)
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The Medial Preoptic Area (MPOA) is activated by testosterone and is essential to the activation of male sexual behavior
Microinjection of dopamine antagonist into the MPOA
Intact male Decrease in sexual behavior
Intact male Sexual (copulation) behavior
Increase of dopamine in the MPOA
Hull et al. 1999; Behav. Brain Res
Pre-copulation Copulation Copulation
INTACT= Non-castrated (normal) CAST= Castrated COP= Copulate TP= Testosterone treatment
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The Coolidge Effect
Novelty re-arouses sexual behavior
A male mice/rat has copulated to satiety can be induced to mate again if the initial female is replaced with a novel receptive female.
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Fiorino et al 1997; J. Neurosci
Dopamine fluctuations in MPOA during the “coolidge effect”
Female 1 Female 2
Dopamine
metabolites
Dopamine
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Are the same brain regions regulate aggressive and sexual behavior?
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Labeling neuronal activity by measuring level of immediate early gene (cFOS)
following sexual or aggressive behaviors in males
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VMH brain region involve in female sexual receptivity (lordodisis behavior)
Pfaff and Sakuma 1979; J Physiol
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Labeling neuronal activity by measuring level of immediate early gene (cFOS)
following sexual or aggressive behaviors in males
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Neuronal manipulation using Optogenetic
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Activation of aggressive using optogenetic in the VMH
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Reversible method to induce aggressive using optogenetic+pharamcolgy
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Anderson, 2012; Biol Psychiatry
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Pair bonding and social behavior in voles
Prairie voles
Highly social
Monogamous
Spend more than 50% of
their time interacting with
other prairie vole
• Montane voles
• Avoid social contact except for
the purpose of mating
• Polygamous
• Spend only around 5% of their
time socially interacting.
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Hemanth et al 2006 Physiology
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Prairie voles have high levels of OT receptor in the nucleus accumbens and the basolateral amygdala relative to montane voles
Montane voles have high levels of receptors in the lateral septum.
Prairie voles have high densities of
the V1a subtype of the AVP receptor in the ventral pallidum and the medial amygdala compared with montane voles.
Montane voles have much higher levels of receptors in the lateral septum than do prairie voles.
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Isoleucine
Phenylalanine
Argenine
Leucine
Neurophysiology of Oxytocin (OXT) and arginine vasopressin (AVP)
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Neurophysiology of Oxytocin (OXT) and arginine vasopressin (AVP)
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Neurophysiology of Oxytocin (OXT) and arginine vasopressin (AVP)
• Oxt and Avp are synthesized in magnocellular neurons in the
paraventricular and supraoptic nuclei of the hypothalamus.
• Oxt and Avp are processed along the axonal projections to the posterior lobe of the
pituritary, where they stored in vesicles and released into the blood circulation.
• In addition, there is dendritic release of the neuropeptide into the extracellular space,
resulting local and diffuse action through the brain to reach distinct targets
• Smaller paraventricullar neurons in the paraventricullar nucleus also produce
the neuropeptides and project directly to other brain regions.
• Mammals have 1 receptor of Oxt and 3 receptors of Avp (AVPR1A, AVP1B, AVPR2).
• In the brain, Oxt and Avp travel along the axonal projection of the paraventricular of the
hypothalamus to different brain areas including: amygdala, hippocampus, striatum,
supriachiamatic nucleus, bed nucleus of stria terminalis and brainstem
• Both peptides have peripheral and central functions
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Oxytocin and parental behavior in Prairie voles
Oxytocin receptor level
High
Parental behavior
Low
% o
f fe
male
show
ing n
urt
uring b
ehavio
r
Ross and Young, 2009
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Prairie vole
Montane vole
Oxytocin and partner preference in Prairie voles
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Viral over-expression of Oxytocin receptor in the NAc of female prairie voles
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Hammock & Young, 2005 Science
V1aR
Vasopressin receptor and pair bonding in Prairie voles and Montane voles
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Lim & Young 2006 Horm & Behav
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Meadow voles (Microtus pennsylvanicus) Prairie voles (Microtus ochrogaster)
Young et al. 1999 Nature
♂
Promiscuous social behavior
Monogamous social behavior
“A single gene can turn the Don Juan of voles into an attentive home-loving husband”. BBC news
The “Fidelity gene”
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?
Walum et al 2008, PNAS
The “Fidelity gene” in human
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2011 DSM-V: clarified better the symptoms
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Autism Spectrum Disorder
Must meet criteria A, B, C, and D:
A. Persistent deficits in social communication and social interaction across contexts, not accounted for by general
developmental delays, and manifest by all 3 of the following:
1. Deficits in social-emotional reciprocity; ranging from abnormal social approach and failure of normal back and forth
conversation through reduced sharing of interests, emotions, and affect and response to total lack of initiation of social
interaction,
2. Deficits in nonverbal communicative behaviors used for social interaction; ranging from poorly integrated- verbal and
nonverbal communication, through abnormalities in eye contact and body-language, or deficits in understanding and use of
nonverbal communication, to total lack of facial expression or gestures.
3. Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers);
ranging from difficulties adjusting behavior to suit different social contexts through difficulties in sharing imaginative play
and in making friends to an apparent absence of interest in people .
B. Restricted, repetitive patterns of behavior, interests, or activities as manifested by at least two of the following:
1. Stereotyped or repetitive speech, motor movements, or use of objects; (such as simple motor stereotypies, echolalia,
repetitive use of objects, or idiosyncratic phrases).
2. Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change;
(such as motoric rituals, insistence on same route or food, repetitive questioning or extreme distress at small changes).
3. Highly restricted, fixated interests that are abnormal in intensity or focus; (such as strong attachment to or
preoccupation with unusual objects, excessively circumscribed or perseverative interests).
4. Hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment; (such as apparent
indifference to pain/heat/cold, adverse response to specific sounds or textures, excessive smelling or touching of objects,
fascination with lights or spinning objects).
C. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited
capacities)
D. Symptoms together limit and impair everyday functioning.
American Psychiatric Association
DSM-5 Development (Jan, 2011)
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Autism Spectrum Disorders
Main characteristics:
Social and Communication Deficits
Fixed Interests (Rigidity in habits)
Stereotypic (repetitive) Behaviors
Symptoms must be present in early childhood
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1 in 130-160 (1 in 94 boys)
Prevalence
Present cross-culturally and cross-nationally
4:1 male to female ratio
• Complex genetic disorders (i.e. interactions between many genes and environmental factors)
• Few hundreds of genes were associated with autism
• No biomarker for autism diagnostic: diagnostic is based only behavioral smyptoms (~1.5-3years old)
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Autism Spectrum Disorders
Pervasive Developmental Disorders
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Studying autism using mouse models
• Multiple genetic modified mouse models
• Multiple behavioral assays and paradigms for studying autistic-related behavioral phenotype
• Autistic-related behaviors are largely scored by human observer (in particularly social interactions)
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Sociability Cognitive rigidity Stereotypical
behavior
Commonly used tests
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Brodkin et al 2004 Brain Research
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Social behavior test for mice
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Cognitive rigidity Wet T-maze assay
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Stereotypic behavior
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Silverman et al 2010; Nature Reviews Neuroscience
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Studying the role of oxytocin in autism using mouse models
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Oxytocin KO mouse model
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Olfactory habitutation/dishabituation
Oxytocin KO
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Ferguson et al 2001; J Neuroscience
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Oxytocin Receptor Knockout and Autism
Pobbe et al 2012; Hormones and Brhavior
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Summery:
OTKO mouse fail to habituate to, or recognize, a stimulus mice even
after repeated exposures.
The deficit in social recognition in OTKO mice represents a defect in
the initial processing of olfactory cues and not in the recall of the
previously stored memory.
OT must be present in the MeA during the initial social exposure for
the proper processing of the olfactory information and the
development of the social memory.
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Oxytocin effects on humans