Behavioral Neuroscience II
Dopamine in Obesity
• Measured the availability of D2 receptors in the brain using PET and [11C] Raclopride
• Obese subjects had significantly reduced [11C] Raclopride binding in the Striatum
o Less D2 receptor availability
• The availability of dopamine D2 receptor was decreased in obese individuals in proportion to
o Lowest D2 values had the largest BMI
o D2 receptor antagonists leads to eating more
o Inhibiting dopamine leads to eating less
o Best explanation is not a lack of D2 receptors, but an inhibited activity.
• Dopamine signals reward
• Dopamine signalling deficiency in obese individuals may encourage pathological eating as a
means to compensate for decreased activation of dopaminergic circuits
• In line with this, obesity is one of the best known side‐effect of antipsychotic drugs (bipolar
disorder, schizophrenia) that exert their actions mostly via antagonism of D2 dopamine
Week 6, Class 1: Hormones and Sexual Behavior
Two types of glands in the body:
• Exocrine glands
o Release chemicals through ducts
Proteins, mucus, includes sweat and salivary glands
• Endocrine glands
o Sex hormones are released by endocrine glands (Primary function is the release of
hormones as opposed to stomach, intestine,…)
Released directly in blood stream
Travel in the blood stream to target
Produce a body’s reproductive cells.
• produce sperm • produce ova (egg cells)
Sex hormones: Sex hormones:
• Release androgens (testosterone) • Release androgens (testosterone)
• Release estrogens (estradiol) • Release estrogens (estradiol)
• Release more androgens than estrogens • Release more estrogens than androgens
• Release progestins (progesterone) • Release progestins (progesterone)
2‐ Adrenal glands
Outer cortex produces small amounts of all sex hormones
Inner medulla does not produce sex hormones.
Responsible for others such as adrenalin and noradrenaline.
Note both men and women produce all hormones
• Men simply release more androgens than estrogens.
• Women release more estrogens and progestins
Hormones and sexual behavior:
• 3‐Pituitary Gland (anterior) :
o Does not produce sex hormones
o Produces tropic hormone:
Primary function is to influence
release of hormones from other
o Located under the Hypothalamus
o Pituitary tropic hormones that travel to
the gonads to stimulate the release of
Follicle‐Stimulating Hormone (FSH)
and Luteinizing Hormone (LH)
o Released by anterior pituitary
Gonadal and Gonadotropic hormones levels
• Cycle in women (cycle that repeats itself every 28 days)
• Steady in men
o Released in pulses (few minutes) several times a day
Menstrual cycle review:
• Follicular phase: FSH will cause maturation of follicles in the ovary
• One becomes dominant Follicle, others degenerate
• Ovulation: In response to a surge in LH and estrogen, Dominant follicle releases an egg (egg
• Follicle becomes the Corpus Luteum (temporary endocrine organ whose main function is to
• Progesterone causes thickening of the endometrium (of the inner lining of the uterus) to
prepare for an eventual pregnancy (Fertilization of the egg by a sperm and implantation of
• If fertilization does not happen, the Corpus Luteum degenerates.
• Causes drops in Estrogen and Progesterone layers
• Causes shedding of the endometrium and menstrual bleeding
~~~~ Anterior pituitary releases gonadotropins
~~~~ Gonadotropins stimulate the release of sex hormones
Are inherent differences between male and female anterior pituitaries the basis for the difference
between male and female patterns of gonadal and gonadotropic hormone release?
Geoffrey Harris in 1950s
• Removed cycling pituitary from mature female rat and transplanted it in a mature male:
became a steady‐state pituitary!
• Removed steady‐state pituitary from mature male rat and transplanted it in a mature
female: became a cycling pituitary!
Patterns of hormone release are controlled by some other part of the body: which one?
The hypothalamic control of the pituitary
1. Release of vasopressin (ADH) and oxytocin from the posterior pituitary
o Both hormones are synthesized in the cell bodies of neurons in Paraventricular
Nucleus and Supraoptic nucleus of the Hypothalamus
o Both affect social responses.
o Oxytocin stimulates uterine contractions during labor
Also considered to be the “love” or “trust” hormone.
2. Release of Gonadotropins by the anterior pituitary Gland except that:
o The anterior pituitary receives no neural input from the Hypothalamus or any other
area of the brain !!!
The hypothalamopituitary portal system
• A portal vein connects the capillaries network in the hypothalamus to the one in the anterior
• Harris (1955) study:
o Cutting the portal vein of the pituitary stalk disrupts the release of anterior pituitary
• Hypothalamus releases the gonadotropin‐releasing hormone
o Induces release of FSH and LH by the anterior pituitary
Review: Three types of hormones:
1. Amino acid derivatives (ex Norepinephrin)
o Synthesized from an amino acid molecule in a few simple steps
o Act as hormones when they diffuse into the blood stream and travel to their tarets.
2. Chains of amino acids (peptides and proteins)
o Cannot diffuse through the lipid bilayer
o Bind to receptors at the cell (mostly GPCRs) surface to activate an intracellular
Follicle‐stimulating hormone (FSH), Luteinizing Hormone (LH), vasopressin,
oxytocin, Gonadotropin‐releasing hormone, melanocyte‐stimulating hormone
MSH), Ghrelin, cholecystokinin (CCK).
3. Steroid hormones
o Sex hormones synthesized from cholesterol
o Lipid‐soluble molecules
o Diffuse through the lipid bilayer
o Receptors located in the cypoplasm or the nulceus
o Affect gene transcription (production of specific proteins)
o Three main groups:
• Developmental effects:
o Influence the development from conception to sexual maturity (permanent)
• Activational effects
o Activating the reproduction‐related behavior in sexually mature adults (temporary)
Gonadal hormones are involved in the expression of sexual behavior
• Ancient history:
o Castration decreases sex drive and fertility • First experiment –1849 Berthold
o Castrated young chicks and observed effects on adult Roosters
Castration lead to decrease in male behaviour and secondary male
o Re‐implantation restored previous condition
Castration – Caponization
Castration & Reimplantation of testis – Normal male development
History of Sex Hormones and Behavior
• First demonstration of hormone replacement therapy
o 1889, a 72 yr old physician, Brown‐Séquard
o Reported increased virility after injecting himself with extracts (using water) from
guinea pig & dog testes
omptes rendus de la Société de biologie, 1889; 41: 415‐422
• But steroids are not water soluble ~~~> placebo effect
Activational Effects of Estrogen
• 35 women 21‐37 yrs in 3 groups:
1. Subjects taking birth control pills: suppression of ovulation and of estrogen increase
2. Subjects using intrusive methods: diaphragm, foam, condom
3. Subjects using non‐intrusive methods: Intrauterine device and male vasectomy
• Conclusion: Women exhibit peaks of sexual activity at ovulation due to the estrogen surge
Testosterone in Women
• Women produce 10~ X less Testosterone than men
• Plasma testosterone levels correlate with women’s
‘sexual desire, sexual thoughts and anticipation of
sexual activity’ (Alexander & Sherwin, 1993)
• Oophorectomy + hysterectomy: sexual desire is
o Administration of Testosterone increases
sexual desire/interest (Sherwin et al, 1985)
• Tuiten et al (2000):
o Study on 8 healthy women (tested within
10 days of the end of their menstrual
o Testosterone was administered in one dose
o Testosterone increased sexual arousal with
a time lag: best explained by the
involvement of brain mechanisms that
regulate sexual behavior Gonadal hormones act on the brain
• Sexual Behavior is influenced by Gonadal Hormones.
• Positive or Negative feedback will influence the subsequent release of hormones
Neural Mechanisms of Female Sexual Behavior
• Ventro‐Medial Hypothalamus (Ventro‐Medial nucleus of the Hypothalamus) is the best
o Fos Protein is produced when Fos is activated.
And immediate early gene
One of the first to be transcribed in response to extracellular signal
Can be used as a measure of neuron activation in the brain, in response to sex
• Medial Amigdala
o Mating activates neurons
o Somatosensory information, such as tactile information from the genitals is sent to
the Medial Amygdala and VMH
o Chemosensory Information is also sent to both areas
• Medial Amygdala projects to the VMH
• VMH sends information to the PAG (Periaqueductal Gray Matter) in the brain stem/midbrain
• PAG progects to the nPGi in the lower brain stem/medulla
o Signals are sent through the spinal cord to control sexual behavior
o Sexually dimorphic projections
Opposing effects in males/females
Female rat sexual behaviour
• Estrous cycle ~ 4 days
o Reabsorbtion of endometrium
• Sexual behavior
o Receptivity ‐ ability and willingness ‐ lordosis behaviour
o Proceptivity ‐ eagerness, active approach, e.g. hopping movements
• Electrical stimulation of the VMN increases lordosis in female rats
o Stimulating the Medial Pre‐Optic Area (mPOA) inhibits lordosis
• Lesioning the VMH decreases female lordosis
• Estradiol implants in the VMH of ovariectomized female rats restored sexual behavior
o Adjacent to VMN: less effect
o Other areas of the brain more than 0.25 mm from VMN: No significant effect
• mPOA: medial preoptic area; APOA: anterior preoptic area; VMN and VMH: ventromedial nucleus of
the hypothalamus; DBB: diagonal band of Broca; LQ: Lordosis quotient. Sollicitation behavior: darting,
hopping, and ear wiggling
• Estrogen treatment increases dendritic spines in the Ventromedial Hypothalamus
o Also increases the number of Synapses in VMH
o A nice example of brain plasticity
Brain can undergo morphological and structural changes in response to extracellular
Estrogen action on reproductive behavior involves morphological changes in the VMH
• Spine density is plastic in a manner that correlates with reproductive behavior.
o In particular, the density of dendritic spines on VMH neurons fluctuates during the estrous
• In ovariectomized rats, VMH spine density increased twofold after estradiol treatment
• Thus, modulation of spine density in the VMH in response to estrogen might cause changes in
Neural Mechanisms of Male Sexual Behavior
• Best‐Studied Areas:
o Bed nucleus of the Stria Terminalis (BNST)
o Medial Preoptic Area of the anterior hypothalamus
• In male rats, Somatosensory Information projects first to the Central Tegmental Field
o Located in the Brain Stem
o Projects to the Medial Preoptic Area & Medial Amygdalla
• Medial Amygdala progects to the BNST & Medial Preoptic Area
• Medial Preoptic Area will send progectrions to the PAG & PGi
• Controls Sexual Behavior in male rats.
Electrical stimulation of the mPOA accelerates copulation in male rats
• Accelerates the pace
o Less mounts and less Intromissions were needed to achieve ejaculation
mPOA Stimulation induces Mounting in Female Rats
• Electrical stimulation of the mPOA inhibits lordosis in female rats
• In sexually naïve ovariectomized female rats injected with 2.5 mg/kg/day of testosterone, daily
stimulation of the mPOA induced mounting of other females (male‐like sexual behavior).
o Female rats began to mount other females
o 10 days post‐testosterone gave a drastic effect
mPOA lesions inhibit sexual behavior in male rats
• Less mounting, intromission and ejaculation
• However, motivation for copulation remains!
o The motivation / desire to engage in sexual behavior remains largely intact in mPOA lesioned
Want to engage in sexual behavior, but don’t quite know how to do it.
• mPOA lesion effect seen in rats,ice, guinea pigs, dogs, goats, lizards, fish, and rhesus monkeys…
Experimental set‐up for the second‐order schedule of sexual reinforcement
• The male is responding on one lever in the chamber and by just having completed a small fixed ratio,
has caused the stimulus light above the right lever to be illuminated.
• The female is situated in the small trapdoor box in the roof of the apparatus.
• Following completion of the first fixed ratio of responses, the trapdoor opens and the female
automatically enters the chamber.
• Copulation is then allowed to occur
Lesion of mPOA vs. Amygdala vs. Castration
• Lesions to the mPOA disrupts the ability to coordinate sexual behavior
o Does not disrupt motivation to engage in sexual behavior
• Lesions to the amygdala disrupted the motivation/desire to engage in sexual behavior
o Animals were pressing the levers less
o However, when female was present, copulation occurred.
• Castration disrupted both mechanisms
BNST necessary for copulation: lesions inhibit copulatory behavior
• Just like lesioning of the mPOA
o More mounts & Intromissions required
o Less Copulation seen
Suppression of an estrogen receptor in the mPOA inhibits mating in male rats
• Used RNAi to inhibit the synthesis of the estrogen receptor protein
o Suppressed ER – Decreased mount frequency and decreased intromissions
Sexually Dimorphic Neurons in the Ventromedial Hypothalamus Govern Mating in Both Sexes and Govern
Aggression in Males
• Using a genetic strategy, Progesterone‐Receptor‐expressing neurons located in the ventromedial
hypothalamus (VMH) were specifically destroyed.
o Ablation of these neurons reduced sexual behavior
Females rejected male more often.
• Lower receptivity
• Decreased Lordosis events
Sexually Dimorphic Neurons in the Ventromedial Hypothalamus Govern Mating in Both Sexes and Aggression
• Ablation of PR+ VMHvl neurons in males reduces mating
o (Progesterone Receptor positive neurons in the Ventromedial Hypothalamus)
o Males show less mounts, less intromissions, mean duration of intromissions is lower. Sexually Dimorphic Neurons in the Ventromedial Hypothalamus Govern Mating in Both Sexes and Aggression
• Ablation of PR+ VMHvl neurons in males reduces aggression as well
o Resident‐Intruder paradigm.
Reduced # of Attacks, duration of attacks
Increased time between attacks
Medial Pre‐Optic Area
o In males, lesions decrease sexual behavior.
o In males, stimulation increases sexual behavior.
o Larger in males than females
Due to testosterone surge around birth
Bed nucleus of the Stria Terminalis
o In males, lesions decrease sexual behavior.
o Projects to the mPOA.
o Larger in males than females.
o Lesions facilitate male sexual behavior.
o Receives serotonergic projections from the PAG. (periaqueductal Gray)
o Ablation of Progesterone Receptor positive neurons inhibits male sexual behavior
o In female rats, stimulation decreases lordosis and can induce mounting.
o Smaller in females than males.
o Lesions attenuate female sexual behavior.
o Receives seroton