Schedule for remaining classes: 4/11/16: 3 rd learning/memory, intro to sex differentiation in nervous system development 4/13/16: Sex differentiation in nervous system development; intro to Presenilins and Alzheimer’s disease 4/18/16: Dr. Doug Portman– genetic sex determination in the nervous system 4/20/16: Presenilins from development to neurodegeneration 4/25/16: Presentations (1hr), with short review session 4/27/16: Exam 3 5/2/16 (9-11:30): Presentations 5/4/16 (9:30-11:30): Presentations
LFS: <0.1 Hz HFS: 100 Hz (brief) Long-term potentiation: functional model for explicit memory *increased EPSP amplitude maintained for >60 min
Long-term potentiation in CA1 is highly afferent-specific
Cooperativity: activation of multiple afferents (NMDAR- dep) Synapse selectivity: only the active afferents will be potentiated Associative: requires simultaneous pre/post activity to depolarize postsynaptic cell LTP in the Schaffer collateral pathway requires:
Spaced stimuli give larger sustained EPSP amplitude (LTP) vs. one tetanic stimulation
Hippocampal neuron LTP requires simultaneous afferent activity and postsynaptic depolarization
CamKII Postsynaptic depolarization activates CamKII & leads to greater numbers of AMPARs in postsynaptic membrane
CaMKII activity is regulated by Ca 2+ -calmodulin binding to release regulatory “hinge”
LTP may not rely solely upon new AMPAR insertion, but also enhanced NT release probability
The number of NT release events increases after LTP induction
Multiple spaced trains, or stimuli, leads to late-phase LTP; one train evokes smaller increase in EPSP for less time
Genetic blockade of PKA eliminates late-phase LTP
Early-phase LTP does not require CREB activation, synapse growth
Synaptic structural changes in L-LTP include new AZs, PSDs
Similar to LTP, long-term depression (LTD) is afferent-specific in CA1 *low-freq tetanus
Different levels of Ca 2+ influx activate either kinase or phosphatase activity at the postsynaptic terminal
Amount of NMDAR activation correlates positively w/ LTP & negatively w/ LTD
Govindarajan et al. Nature Reviews Neuroscience 7, 575–583 (July 2006) | doi: /nrn1937 *capture associativity betw.1-2 and 3 3: L-LTD 1,2: L-LTP LTP and LTD proteins are generated in response to LTP stimuli & influence plasticity of nearby synapses potentiation tags capture LTP proteins
The Morris water maze learning & memory test requires NMDAR
Transcriptional control by enhancers and repressors
promoter Conditional deletion of NMDA R1 subunit (NR1) in CA1 neurons by Cre-lox
CA1-specific Cre; NR1 cKO mice have defective LTP, memory
promoterMutant gene Constitutive activation of CaMKII kinase until Dox shuts it off
Persistent activity of CaMKII interferes w/ learning & converts LTP to LTD
Hormone-dependent sexual differentiation in the nervous system
Testis-determining factor (TDF, aka SRY) changes the default ovary-generating program SRY: SOX homeobox TF, upregulates other TFs seminiferous tubules
before testes: Mullerian & Wolffian ducts Reproductive system is generated intersex and becomes specified by hormones
Gonadotropin-releasing hormone in hypothalamus releases FSH, LH from pituitary GnRH1: essential for both ovulation (female) & spermatogenesis (male) testosterone: prohormone for DHT, estradiol
Estradiol, essential for masculinization of the rat brain, has many receptors in the POA and anterior hypothalamus
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
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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