Neurosecretory cells in hypothalamus stimulate/inhibit pituitary
hormone release via pituitary capillary bed
Estradiol surge causes high LH, FSH at ovulation
Castration + estrogen leads to female behavior; testosterone
in female causes male behavior
Testosterone is converted to estrogen by aromatase; estrogen
binds to ER and regulates transcription
psych.unn.ac.uk
The spinal nucleus of the bulbocavernosus: sexually dimorphic
neurons innervating the perineal muscles
Females have very few SNB motoneurons, perineal muscles
Injecting female with testosterone causes sparing of SNB
neurons, perineal muscles
Castration + androgen blocker in males: female-like SNB,
perineal muscles
The lumbar region of the spinal cord in females lacks a SNB
Cell Death in the SNB
Testosterone binding to AR increases trophic factors & SNB
survival
The POA is 6x larger in male hypothalamus
The corpus callosum & anterior commissure are larger in females
sexuallydimorphic
nucleus (of
POA): larger in
males
However, females given testosterone will develop a larger SDN
in the preoptic area similar to males
Castration at P1 will reduce the male SDN size
Diencephalic E14 neurons display sexual dimorphism prior to
gonad specification
Female E14 diencephalic neurons express prolactin; male
neurons do not
Development of VCRs & song is dependent on steroid hormones
blue= vocal control regions in zebra finches
zebra finches: VCR size is fixed early w/ hormones
canaries: VCR size increases in spring (androgen surge in spring), &
decreases in the fall
Sex differences in the avian song system
*RA nucleus is smaller in female brain
Male songbirds show gradual increase in size of VCRs HVC &
RA post-hatching
Development, Growth & Differentiation
Volume 53, Issue 2, pages 213–224, February 2011
An early critical period of HVc and RA development exists
Gynandromorphic zebra finches have sexually dimorphic gene
expression in brain
HVC +
AR mRNA
probe
ASW W
chromosome
(female) gene
expression
Structural changes in spine density and shape after estradiol
(testosterone) treatment
Estradiol acts directly on spine morphogenesis & indirectly via
transcriptional changes
Neuronal differentiation and death in the brain
from development to old age:
the Presenilin story
1. Presenilins in early brain development
2. Presenilins in mature neurons
2. Presenilins in neurodegeneration
Presenilins and Alzheimer’s disease
Late-onset AD:
~90% of AD cases
a few causative genes known (eg. ApoE4)
onset 65+ yrs.
Early-onset AD: ~10% of AD cases
may have a genetic component (linkage on Chr. 14)
onset between 25-50 yrs.
Familial AD:
~1% of AD cases
strong genetic component
early-onset dementia
Presenilins:
early-onset AD (25-50 yrs.)
mutated in 90% of familial AD (or FAD)
The Alzheimer’s brain and AD
Alois Alzheimer (1906)
Amyloid precursor protein, apolipoprotein E, presenilins, tau
Theories of AD: cholinergic hypothesis, amyloid hypothesis, tau hypothesis, vascular
hypothesis, presenilin hypothesis
Drugs for AD patients: memantine (NMDAR non-competitive antagonist), A beta
vaccine, acetylcholinesterase inhibitors (Aricept)
Intracellular tangles and extracellular plaques in Alzheimer’s
brains
Cognitive deficits in Alzheimer’s disease
-Loss of recognition of familiar people
-Confusion about time
-Difficulty remembering location of home, purpose of
common items
-Difficulty making decisions
The many functions of Presenilins
Presenilins: part of the gamma-secretase complex
A very sticky protein: A beta forms oligomers, then plaques
PS1 mutations are distributed throughout the coding region
Presenilins during CNS development
Presenilin-1 is essential during CNS development
PS1-/- phenotype:
-perinatal lethality
-enlarged brain ventricles
-brain hemorrhaging
-loss of ventricular zone
Cranial hemorrhaging defects in PS1-/- embryos by E12.5
The Zlokovic vascular hypothesis of Alzheimer’s disease
*observed vascular defects in AD patients
Cell cycle deficits in PS1 cKO; PS2-/- forebrain
Cell cycle reentry in Alzheimer’s disease neurons
PCNA+ neuron
AD neuron: 4n
AD tg mouse:
cyclinD+ CA1 neuron