Hypothalamus: love, trust, aggression, addiction Flashcards
What animals are instrumental in understanding the role of the hypothalamus in SOCIAL behaviours?
What discovery made looking at these animals?
Prievoles
2 hypothalamic neurons important in social behaviours: Oxytocin+ (Oxt) and Arginine Vasopressin+ (AVP) neurons in the PVN
What are social behaviours?
Trust, aggression, empathy, love
Where are Oxytocin+ and Vasopressin+ neurons present and where do they project to?
The PVN of the hypothalamus
Project to the POSTERIOR PITUITARY and release hormones directly into the blood stream –> periphery
(ASIDE) What are the other types of neurons in the PVN?
Hormone releasing (eg. CRH) - to ME
As well as to the periphery, where do Oxt and AVP neurons project to?
To many different target neurons (express receptors) of the brain in complicated central circuits
What is AVP important in?
What is Oxytocin important in?
The regulation of kidney function and water balance
Parturition (birth) and lactation
Recent studies show both are highly important in directing social behaviours
How are Oxt and AVP important in directing social behaviours?
Through the complex interaction with other brain regions and neurons that are stimulated by these hormones centrally
Who studies prievoles?
What did they find?
Carter and Young
Prievoles:
- SOME vole strains form a PAIR-BOND- form close attachment with a mate and males show good paternal behaviour - maintain close bond for rest of lives
- OTHER strains do NOT form a pair bond - polygamous and ignore offspring
What dictates the behaviour of the Prievoles?
1) BALANCE of Oxt and AVP
2) LOCATION of neuorns that express Oxt and AVP RECEPTORS (balance of where neurons receive Oxt and AVP)
(WHERE and HOW MANY neurons are stimulated –> give rise to different behaviours in voles)
Why do some vole strains form pair-bonds?
Neurons rich in Oxt receptors are found in areas that govern ADDICTIVE BEHAVIOURS –> become ADDICTED to their mates
What can generate diversity in the brain and sociobehaviours traits?
Microsatellite instability:
- Determines how strongly the AVP RECEPTOR gene is transcribed (expressed)
What is a microsatellite?
- Non-coding enhancer-like regions that control how much of a gene is transcribed
- Repeated unit
What is the structure of the vasopressin RECEPTOR gene?
- 2 exons (exon 1 and exon 2)
- Microsatellite region upstream of exon 1 - controls how much of the vasopressin RECEPTOR gene is transcribed
What is the difference between the microsatellite region of AVP in different voles?
Different NUMBERS of repeat units
What is the difference in function between long and short microsatellite regions?
How was this seen?
LONG satellite region - regulates MORE AVP RECEPTOR gene transcription
Seen by:
- Cloning the different satellite regions UPSTREAM of a reporter gene
What is the difference in behaviours of voles with a long or short satellite region?
NO DIFFERENCE in:
- Nesting
- Nursing posture
- MATERNAL pup-grooming
SIGNIFICANT DIFFERENCE in:
- PATERNAL pup-grooming
- Long satellite region - better fathers (lick and groom their pups for longer)
What are the differences in paternal behaviour with a long satellite region?
How is this seen?
Greater probability of SOCIAL ENGAGEMENT and BONDING with other voles
Chamber experiment:
- Voles to test with 2 chambers: one containing original mate and one containing a new mate
- See where spends the most time
- Spend more time with the original vole of whom they are pair bonded
What is the hypothesis with longer satellite regions and AVP receptor activity?
Longer satellite regions alter AVP receptor activity
What are the GENOTYPE differences in social behaviour associated with?
- Robust differences in how AVP binds to V1aR in the brains of F1 males
- Several brain regions –> 50% change in quantity of V1aR binding
Long allele:
- In brain region associated with addiction –> gives a HIGH level of receptor binding
What associates with pair-bonding in humans?
Where was this seen?
Genetic variation in the vasopressin receptor 1a gene (AVPR1A):
- Comes in many different forms in humans
Swedish study:
- Men with 2 copies of one particular form of the gene (homozygous for RS3 334)
- -> Less likely to married and more likely to report difficulties in their relationships than other men
What does the imbalance of Oxy and AVP cause?
Example
Effects on health and wellbeing
Work connects reduction in Oxy functionality?? to addiction and autism
What social behaviours does Oxy control?
Trust, empathy
What social behaviours does AVP control?
Aggression
What is a new target for substance-use disorders?
Brain Oxy system
What do drugs acting on the Oxy brain system ameliorate?
Range of ADDICTIVE behaviours:
- Alcohol
- Stimulants
- Opioids
- Nicotine
What does Oxy inhibition of drug consumption and drug reward involve?
Interference with the brain reward circuitry (in particular dopaminergic systems in the striatum)
What does synthetic Oxy cause?
How?
Interference with stress responses and socioemotional impairments during protracted withdrawal
Inhibits stress-induces relapse by compensating for impaired Oxy functionality and to REBALANCE:
1) The specific dopaminergic pathways
2) Hypothalamic and extrahypothalamic stress systems
What is the effect of increases in Oxy on the brain?
Enhancement of connectivity between:
1) The frontal cortical regions
2) Amygdala and Nucleus Accumbens
–> Criticial to Oxy effect on relapse by improving inhibitory control over craving and cue reactivity
How are their differences in key neurons?
Over life and in sex-specific manner
What do sex differences in behaviour come from?
Assumed arise from sexual dimorphism in the underlying neuronal circuits
Examples in sex differences in behaviour in mice?
What is different in the brains of these mice?
When exposed to alien pups:
- Virgin females behave maternally
- Males attack or ignore the pups
Differences:
- TH expressing neurons in the AVPN of the mouse hypothalamus are more numerous in mothers than in virgin females and males
- -> Governs paternal behaviours in a sex-specific manner
What happens in female mice if ablate the AVPN TH+ neurons?
Impairs maternal behaviour
What happens in female mice if optigenetically stimulate/increase AVPN TH expression?
ENHANCES maternal care
What happens in mice if reduce TH in mice females?
Increase TH?
What is the conclusion from this research?
Reduce:
- Reducing circulating Oxy
Increase:
- Increasing circulating oxytocin
Conclusion:
- AVPN TH+ neurons control oxycytocin secretion and maternal care
- Causal relationship between sexual dimorphism in the adult brain and sex differences in paternal behaviour
Where do AVPN TH+ neurons have a monosynaptic connection to?
Oxy+ neurons in the PVN
How does the AVPN TH+ neurons effect males?
No effect on paternal care but SUPRESSES inter-male aggression
How does the body deal with pregnancy in a mouse?
In a female, get new neurons born as needed to support pregnancy –> neurons born in order to ANTICIPATE change and prepare the body optimally for changes
What are the VMN and DMN of the hypothalamus involved in?
Agressive behaviours
What is another reason why are male mice more aggressive than female mice?
Male mice have a class of neurons that make them more aggressive - females don’t
How can you show a particular neuron/circuit is involved in a certain behaviour?
OPTOGENETICS:
- Can activate a neuron expressing the Chr2 gene –> activate a circuit
What is critical to function of a neuronal class?
NUMBER and LOCATION
Where is the telencephalon in comparison to the hypothalamus?
ANTERIOR
What establishes telecephalic and hypothalamic progenitor idenities?
Cross-repression between the transcription factors:
1) Foxg1 (telencephalon)
2) Foxd1 (hypothalamus)
What do foxd1 progenitors ultimately commit to?
Example? How?
Many hypothalamic neuronal identities
Example:
- AVP and Oxy neurons
- Foxd1 progenitors divide and become differentiated –> give rise to more progenitors etc.
- GRADUAL REFINEMENT from foxd1 cell –> neurons of specific nuclei
What does the absence of Foxg1 cause? (homozygous)
Death (embryonic lethality)
What does the absense of Foxd1 cause? (homozygous)
Viable
But display microcephaly, altered hippocampal neurogenesis, behavioural and cognitive defects
What is the hypothesis if have ONE copy of foxg1? (heterozygous)
Why?
Have MORE hypothalamus –> MORE Oxy and AVP neurons
Due to:
- Less foxg1 protein
- Less repression of the foxd1 protein
How was the increase in Oxy and AVP neurons validated?
What did this show?
Immunohistochemistry:
- Showed the number of cells set aside to be telecephalic might be in competition with the number of cells set aside to become hypothalamic
Why need accurate balance between foxg1 and foxd1 expressing territory?
To balance higher cognitive function with autonomic function
What is TH?
Tyrosine hydroxylase - a marker for neurons involving the dopaminerigic neuorns
