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Introduction to Fear Conditioning/Sex Biases, Screenshot 2025-03-14 at 10…
Introduction to Fear Conditioning/Sex Biases
Fear Conditioning
Fear extinction starts with fear conditioning
Extinction: exposure to the feared stimulus without the aversive event. The animal learns that the stimulus should no longer be feared, and fear responses eventually stop.
Measuring the fear responses afterward to determine extinction retention.
The new learning theory:
Fear extinction is an active process involving the formation of a new “safety” (CS-no US) memory that co-exists with the original (CS-US) memory.
How do we know that it’s an active process and not passive forgetting?
Without the extinction training, the fear responses are still present, compared to almost absent fear responses in those who had been trained.
the original CS-US memory still exists after extinction
SPONTANEOUS RECOVERY (TEMPORAL):
the fear memory comes back after a long time.
RENEWAL:
Fear responses will occur if you do a retention test in the same context as acquisition.
Fear responses will remain relatively absent if retention test occurs in the same context as extinction training.
shows that Extinction is CONTEXT DEPENDENT
Why study fear extinction?
A useful model that helps us understand the neurobiological bases of complex memories
Fundamental knowledge > helps us understand how we adapt to changing environments
Exposure therapy > helps us understand how anxiety treatments work
Gold standard for anxiety treatments, based entirely on extinction training.
Relapse > helps us understand why anxiety treatments don’t work all the time.
Often when exposed to a novel environment.
Translation > new discoveries made about fear extinction can be translated to clinical applications.
Medial Prefrontal Cortex (MPFC)
Evidence from rodents and humans of its importance.
RATS
Prelimbic and infralimbic areas are both involved, with
PL having more fear
and
IL having less.
Microstimulation of
IL
(Milad, Quirk (2002))
what did they do?
Microstimulated the IL during extinction training (day 2) > very small electric impulses from electrodes to the brain area.
Paired stim: CS + IL gets buzzed with stimulation to increase its activity
Unpaired stim: stimulation without CS pairing
No stim: nothing
what did they find?
Paired IL stimulation (during CS presentations) reduced fear expression
Paired IL stimulation enhanced within-session extinction (day 2)
Paired IL stimulation during extinction training enhanced extinction retention the next day (day 3)
Unpaired IL stimulation had no effect.
interpretation:
stimulation of the IL DURING CS presentation results in faster extinction with more retention.
Can’t determine that the IL is NECESSARY for memory formation without isolating other factors. > BLOCKING activity in the IL should result in impaired extinction.
Temporary inactivation of
IL
(Sierra-Mercado, Padilla-Coreano, Quirk (2011))
Lesions can be an issue because they’re final.
what did they do?
Temporarily inactivated the IL prior to extinction training (day 2) using muscimol (MUS) infusions (GABA receptor agonist)
what did they find?
IL inactivation did not effect expression of conditioned fear.
IL inactivation impaired within-session extinction (Day 2)
IL inactivation during extinction training impaired extinction retention (day 3) following day.
MUS rats show relapse during test phase.
interpretation:
Impaired IL group is still learning extinction, though much more slowly > could be said that the IL is necessary for within-session (same day) extinction.
:!!:
IL is necessary for extinction, not fear expression (conditioning phase)
:!!:
Temporary inactivation of
PL
(Sierra-Mercado, Padilla-Coreano, Quirk (2011))
what did they do?
Temporarily inactivated the PL prior to extinction training (Day 2) using musimol (MUS) infusions (GABA receptor agonist).
what did they find?
PL inactivation impaired expression of conditioned fear
PL inactivation did not impair within-session extinction (day 2)
PL inactivation during extinction training did not impair extinction retention (day 3) the following day
interpretation: :!!:
PL is needed for expression > drastically reduced fear expression from the first trial. PL NOT NECESSARY for fear extinction.
:!!:
Microstimulation of
PL
(Vidal-Gonzalez et al (2006))
what did they do?
Micro-stimulated the PL during extinction training (Day 2)
what did they find?
PL stimulation marginally increased freezing during within-session extinction (day 2)
PL stimulation during within-session extinction impaired extinction retention the next day (day 3)
interpretation:
activation of the PL during extinction makes the extinction memory worse.
HUMANS
The rodent PL may be functionally homologous to the human dorsal anterior cingulate cortex (dACC)
The rodent IL may be functionally homologous to the human ventromedial prefrontal cortex (vmPFC)
Human fear response is tested through fMRI to see what areas light up (+ size and thickness of structures corresponding to behaviour), through skin conductance.
PFC to PTSD (MIlad et al (2009))
what did they do?
Trauma exposed controls, ptsd patients.
Measured fear responses and brain activity during the “office” fear conditioning and extinction paradigm in people with PTSD and trauma-exposed controls
showing a picture of an office > if the light inside turns on blue its safe, if its yellow then there's a shock.
what did they find?
People with PTSD showed normal fear acquisition and within-session extinction, but impaired extinction retention (fear relapsed)
During extinction retention,
people with PTSD showed hyperactivation of the dACC, and hypoactivation of the vmPFC
interpretation:
could suggest a structural or functional change in the brain that keeps the dACC extra sensitive or in overdrive?
Sex Biases in Neuroscience
and Biomedical Research
Beery and Zucker (2010)
Conducted a survey of 2000 animal studies from 2009. A male bias was found in 8/10 disciplines, most pronounced in neuroscience, pharmacology, and physiology.
A female bias was only found in studies on reproduction and in the few studies that specified sex in immunology (75% of studies from the three top immunology journals did not specify sex.)
Replicable in humans (B).
The bias also exists when studying conditions that are KNOWN to be more common in women than men.
Milad and Milad (2012)
Found that less than 2% of studies were conducted looking at the female brain.
Sex is a set of biological characteristics > chromosomes, hormones, sex organs, and genitalia. Gender is made up of sociocultural influences.
Sociocultural influences still have an effect on the brain (plasticity).
Hard to tell if its an innate difference you’re born with, or a social difference your brain’s adapted to.
Where rat testing comes in handy.
In rats we just refer to sex, in humans we refer to both.
Does sex actually matter?
Don't know why the sex difference exists
Biases in reporting > fewer mental health reports in men due to societal pressures
Sex differences include the way cells metabolise, brain circuits, lung development, etc etc > replicable across species.
Sex differences may mean similar effects, but different effect size:
Lesser extent in males than females of corticotropin-releasing factor activating a brain circuit
(Bangasser and Cuarenta (2021))
Why don’t scientists like studying females?
Women have a menstrual/estrous sample > considered a hassle because you have to test during all phases.
Women are thought of as too variable, which is undesirable as scientists want their variability small, to more effectively find differences between groups.
Males are considered more simple.
Thoughts that there are no meaningful sex differences anyway.
The idea that men are simpler is false > males and females are just as variable as each other, even when they don’t try to reduce variability from the estrous cycle. Sometimes males are more variable than females (metabolism, hormone, morphology)
What are the consequences?
We know that women are 1.5 times more likely to develop an adverse reaction to prescription drugs than men (Kim et al 2010)
The Government Accountability Office in USA released a 2001 report stating that 8/10 drugs most recently removed from market had more adverse effects in women than in men (Adler, 2010)
Both men AND women lose. Women have bad effects from the meds, men get a really effect med for them taken off the market.
In 2000, the FDA removed phenylpropanolamine, a component in many over-the-counter drugs, from all drugs because of evidence of increased risk of bleeding into the brain/tissue around the brain in women but not in men (Pollitzer, 2013)
Early in 2013, the Food and Drug Administration (FDA) ordered the makers of the well-known sleep aid Ambien (zolpidem) to cut their recommended dose in half—but only for women. In essence, the FDA was acknowledging that despite extensive testing prior to the drug’s release on the market, millions of women had been overdosing on Ambien for 20 years.” (Cahill, 2014)
At a fundamental level… Our models of how the brain works to coordinate our thoughts, feelings, and behaviours apply only to a narrow group – we have enormous knowledge gaps that for decades were not even recognised to exist.
Possible solution > Mandates
Since 2006, the Canadian Institutes of Health Research has required scientists across its 13 institutes to analyse sex and gender
From 2014, applicants to the European Commission's Horizon 2020 funding scheme were asked to include sex and gender analysis in their projects
From 2016 applicants for NIH (USA) grants to study vertebrate animals are required to explain how their study design will account for Sex as a Biological Variable. In most cases, this means that proposed studies should include both males and females; single-sex studies require strong scientific justification.
Australia: in 2023, NH&MRC released a draft “Statement on Sex, Gender, Variations of Sex Characteristics and Sexual Orientation in Health and Medical Research (the Statement)” for public consultation
Mandates have had limited success, but a lot of studies in different disciplines still fail to analyse data by sex.
Priority funding calls (driven by funders, government), Ethics approval committees, Journal editors, Peer reviewers (of grants, of manuscripts for publication), Educator, and Science communicators are all needed to step up and make more of an effort about including females in research.
