STRESS, ANXIETY, AGGRESSION

Question 1

What is stress?

Answer 1

Physiological reaction caused by the perception of aversive or threatening situations’-Walter Cannon (1871-1945). Change that causes physical, emotional, or psychological strain. . Physiological responses help prepare for ‘fight-or-flight’ situations. Episodic or continuous. Adaptive, but also harmful

Question 2

Physiology of stress response

Answer 2

Threats require enhanced activity -> need to mobilize energy resources. Sympathetic-adrenal-medullary (SAM) system. The hypothalamus and sympathetic nervous system stimulate the adrenal medulla (kidneys) to release the catecholamine transmitters epinephrine (↑blood glucose) and norepinephrine (↑ blood pressure). Norepinephrine is also secreted in the brain during stress.

Question 3

Stress effects on the brain

Answer 3

Stress can be neurotoxic. Hippocampus -> involved in learning and memory. Chronic exposure to glucocorticoids destroys hippocampal neurons via decreased neurons via decreased glucose entry and Glutamate reuptake -> excessive Ca+ influx and toxicity

Question 4

Evidence for stress-induced neurotoxicity

Answer 4

Rat exposed to cat smell and presence for 75 min. Blood glucocorticoids increased. Impaired primed-burst potentiation (PBD; similar to Long-term potentiation (LTP), synaptic strengthening) in hippocampus. Impaired in spatial task

Question 5

Vervet monkeys in kenya study

Answer 5

have a hierarchical society -> bottom rank monkeys subjected to continuous stress by upper rank -> enlarged adrenal glands (excessive (nor)epinephrine production) -> hippocampal degeneration.

Question 6

What is Post-traumatic stress disorder?

Answer 6

Long-lasting psychological symptoms after traumatic events (e.g. natural disaster, experience of violence) are over. PTSD likelihood is increased if the traumatic event involves danger or violence from other people (assault, war) Symptoms=flashbacks, hypervigilance, irritability, heightened reactions to sudden noises, detachment from social activities. Often triggered by cues (e.g. helicopter sound) related to traumatic event (e.g. war). Learned, conditioned response.

Question 7

PTSD and Brain changes

Answer 7

Reduced size of hippocampus in combat veterans and police officers with PTSD -> Possible risk factor for PTSD

Question 8

Monozygotic twin study - PTSD

Answer 8

Monozygotic twin study from -> Vietnam war (Gilbertson et al. 2002) twin who fought in war than twin who didn’t = smaller hippocampus -> Smaller hippocampus in those with PTSD.

Question 9

Reasons for hippocampal changes to PTSD

Answer 9

Hippocampus plays a role in distinguishing contexts. Inability in PTSD from detecting threatening vs safe contexts, ‘threat generalization’

Question 10

Prefrontal cortex + amygdala in PTSD

Answer 10

Prefrontal cortex (PFC) involved in impulse control and thought to normally inhibit amygdala, involved in emotional expression (Rauch et al. 2006). * PTSD associated with greater amygdala and reduced PFC activation than controls to fearful face (opposite for happy face) – study (Shin et al. 2005). PTSD-related changes may indicate excessive emotional response and reduced inhibitory control.

Question 11

PTSD treatments

Answer 11

Psychotherapy -> associated with decreased amygdala activity and increased PFC hippocampus activity. Antidepressants (SSRIs) -> increased hippocampal volume due to stress relief.

Question 12

Exposure therapy (PTSD treatment)

Answer 12

Learned associations (cue-stress) play a role in PTSD. Cue alone induces a conditioned fear response. Pavlov -> extinction (stage of operant conditioning) learning reduces cue responding.
Cue exposure therapy is highly effective, borrows principles from extinction learning. Repeated cue presentation over weeks in safe therapy context reduces response to cue (learning of non-threat, reduction of fear/anxiety).

Question 13

What is anxiety and anxiety disorders?

Answer 13

Anxiety -> apprehensive uneasiness or nervousness over an impending or anticipated ill. Normal part of life, unlike stress may not have an identifiable trigger, but some similar responses (faster heartbeat, breathing).
However -> Anxiety disorder=more intense fear/anxiety inappropriate for circumstance.

Question 14

Anxiety disorder:

Answer 14

Anxiety disorder -> more intense fear/anxiety inappropriate for circumstance, more than just a temporary worry. Likely due to cumulative effects of stress, contributes to depressive and substance abuse disorders. Women more likely than men to experience. Many types, but panic disorder, agoraphobia, generalised anxiety disorder (GAD), social anxiety disorder have known biological component.

Question 15

What is panic disorder?

Answer 15

Episodic attacks of acute (seconds to hours) anxiety, terror. Symptoms: hyperventilation (low CO2), irregular heartbeat, dizziness, faintness, fear of losing control and dying. Coping with hyperventilation by breathing into paper bag.
Cultural factors play a role as Asian, African, and Latin American Countries have lower rates than e.g. USA (American Psychiatric Association)

Question 16

What is Agoraphobia?

Answer 16

Intense fear or anxiety about leaving home, being in open/public areas, being in lines/crowds, etc. Coping through avoidance of those situations due to disproportionate fear or anxiety. Staying home for years, fear of panic attack

Question 17

General anxiety disorder:

Answer 17

Excessive, uncontrollable worrying and anxiety from a wide range of situations and difficulties controlling these symptoms. Sense of impending danger, sweating, trembling, difficulty concentrating. More prevalent in women than men

Question 18

Social Anxiety disorder:

Answer 18

Persistent, excessive fear of being exposed to the scrutiny of others (e.g. public speaking, group conversations), appearing incompetent. Sweating, blushing. Equally likely in men and women. Cultural component to both (more prevalent in people of European descent than e.g. Asian, Latino, African descent).

Question 19

Brain changes linked to anxiety disorders:

Answer 19

Functional imaging using PET and fMRI shows changes in the prefrontal cortex, anterior cingulate cortex, and amygdala.

Question 20

Brain changes from panic attacks

Answer 20

Increased amygdala activity during panic attack (Pfleiderer et al., 2007) and in response to presentations of faces with anger, disgust, and fear in social anxiety disorder (Phan et al., 2005) -> Activation correlates with symptoms.

Question 21

Brain changes in General Anxiety disorder

Answer 21

Adolescents with GAD exhibit increased amygdala and decreased ventrolateral prefrontal cortex activation (Monk et al., 2008)
Lack of suppression and inactivation of amygdala activation via ventromedial prefrontal cortex (vmPFC) -> PFC plays a role in inhibition of fear.

Question 22

Treatment for anxiety -> GABAergic drugs

Answer 22

Benzodiazepines - agonist
Flumazenil - antagonist
neurosteroid synthesis

Question 23

Benzodiazepines in reducing anxiety

Answer 23

Benzodiazepines (BDZ) reduces anxiety and anxiety-like behaviors in animals.
Less time spent on the ‘anxiogenic’ open arm on the elevated plus maze (EPM).
Binds to the inhibitory GABAA receptor as ‘agonist’. Increases Cl- influx. hyperpolarization
BDZ administration reduces amygdala activity when looking at emotional faces (Paulus et al., 2005)

Question 24

Flumazenil in anxiety

Answer 24

antagonist to benzodiazepines -> disinhibits action at GABAA receptor and produces panic in panic disorder patients. Treats BDZ overdose, acute alcohol intoxication. Abuse potential, withdrawal, sedation. (without BDZ more emotional responses). Better compounds are needed with fewer side effects.

Question 25

Treating anxiety by increasing neurosteriod synthesis

Answer 25

Neuroactive steroids ‘neurosteroids’ (e.g. allopregnanolone) synthesized in periphery and CNS. increase activity of GABAA receptor. During anxiety attacks, neurosteroid synthesis is suppressed, resulting in suppression of GABAA receptor function. XBD173 enhances neurosteroid synthesis and reduces panic, in absence of sedation and withdrawal symptoms (Nothdufter et al., 2011)

Question 26

Compounds that affect the serotonin and glutamate system:

Answer 26

The anti-depressant fluvoxamine, SSRI, reduces panic attacks (Asnis et al., 2001).
Similar findings for D-cycloserine (DCS) an indirect agonist of NMDA receptor (Ressler et al., 2004)
Presumed action by facilitating ability of behavioural therapy to extinguish fear responses.
DCS facilitates extinction of conditioned fear in animals (Walker et al. 2002)

Question 27

What is aggression?

Answer 27

Common across many species. Related to species survival, such as gaining access to mates, protecting offspring. May involve behaviours related to threat (warning), defensive (attack), submission (accept defeat).

Question 28

Brain regions of aggression:

Answer 28

Programmed by brain stem. Electrical stimulation of periaqueductal gray (PAG) elicited aggressive attack and predation in cats. Medial Hypothalamus -> Dorsal PAG: defensive rage
Lateral Hypothalamus -> Ventral PAG: predatory attack. Amygdala nuclei control these pathways (either excites/inhibits PAG).

Question 29

Aggression and Serotonin link

Answer 29

Increasing serotonin and transmission reduces aggression.
Reducing serotonin transmission via destruction of serotonergic axons or reducing serotonin synthesis increases aggression.

Question 30

Monkey study in aggression and serotonin

Answer 30

Low levels of serotonin metabolise (5-HIAA) in cerebrospinal fluid in rhesus monkeys linked with high levels of aggression.
o Picking fights with bigger monkeys
o High risk taking (dangerous leaps)
o Suggests serotonin inhibits aggression and mediates risky behaviours.

Question 31

Human studies of aggression and serotonin

Answer 31

Some (mixed) evidence shows that serotonergic neurons play an inhibitory role (Duke et al., 2013) in aggression. Low 5-HIAA in CSF linked with aggression and antisocial behaviour. SSRI (fluoxetine) has been shown to reduce aggressive behaviour in some cases.

Question 32

Aggression as a reward

Answer 32

Certain individuals exhibit ‘appetitive’ aggression, motivated by intrinsic reward -> Thought to be an adaptation to violent environments. Remaining more functional in violent settings (war afflicted communities, e.g. Ugandan Child soldiers) -> Elevated social status
Animal models allow us to study this behaviour (and brain mechanisms) under controlled conditions. -> Conditioned place preference (CPP) -> Instrumental conditioning.

Question 33

Examining aggression reward in animals:

Answer 33

Conditioned Place Preference (CPP):
Typically used with drug, food, social reward in mice/rats. Before conditioning -> all chambers are neutral stimuli. Conditioning -> One chamber is paired with reward (drug) whereas the other one is not (neutral nothing significant). After conditioning -> After several reward-chamber pairings, reward-paired side acquires motivational significance and acts as a conditioned stimulus. Animal goes back to the rewarding drug chamber and prefers it than neutral. Called place preference.
If a substance/experience is ‘rewarding’ then animals will spend more time in that chamber paired with that substance/experience, i.e. develop a preference for aggression.

Question 34

Conditional Place preference in aggression

Answer 34

Resident vs intruder males -> Male rodents are very territorial after sexual experience and will attack the unfamiliar intruder.
During conditioning -> Resident attacks the intruder in the ‘Paired’ side, no intruder on the ‘Unpaired’ side.
After conditioning -> Resident mouse that exhibited aggression spends more time on the Paired side in the absence of the intruder mouse. Therefore, they have a preference for releasing aggression to intruders on the paired side -> aggression is quite rewarding -> motivated to go there.

Question 35

Operant conditioning for aggression reward

Answer 35

Animals will learn to lever press for food reward in operant ‘Skinner’ chamber -> The reward sustains the lever press response or ‘reward self-administration.’ -> Once trained animals will press lever even in absence of reward or, ‘reward seeking’.
Animals will learn to lever press for ‘intruder’ (aggression self-administration)
* Trained animals press lever even in absence of the intruder (aggression-seeking).

Question 36

Aggression reward brain changes:

Answer 36

The nucleus accumbens (NAc) plays a key role in reward and motivated actions together with the VTA. e.g. Food and drug-seeking
* Activated by rewarding experiences, e.g. drugs of abuse, food, water, and sex.
* Measured by the activity-sensitive protein ‘Fos’.
* Artificial stimulation using ‘optogenetics.’ (forcefully turn on these neurons)
* This same protein activates when aggressive behaviour is enacted.

Question 37

What are immediate early genes (IEGS)?

Answer 37

Strong activity induces ‘immediate early genes’ (IEGs) which are rapidly transcribed to mRNA (20-45 min) and translated to protein product (90-120 min)

Question 38

What is c-Fos or Fos?

Answer 38

c-Fos or Fos is an IEG, it’s protein product ‘Fos’ is used often as a neuronal activity marker -> Detect Fos protein post-mortem in prepared brain tissue slices via immunohistochemistry.

Question 39

Immunohistochemistry process

Answer 39

Brain -> cut slices from brain areas of interested on cryostat -> you can scan the entire brain -> perform immunohistochemistry for Fos and observe under microscope.
Example -> immunohistochemistry detection of Fos reveals cocaine-activated neuronal ensemble. + Aggression SA and seeking activate the Nucleus accumbens (NAc). Nucleus accumbens activate rewards shown in brain scans. These examples are correlational – we also need casual role evidence.

Question 40

What is optogenetics?

Answer 40

Light-induced neuronal activity manipulates using viruses -> virtually transformed neurons with light-sensitive channels called ‘opsins’.
* Blue light turns on the excitatory channel rhodopsin (ChR20 -> Stimulate
* Green light turns on the inhibitory arch-rhodopsin (ArchT)➝ Inhibit.
Optogenetic stimulation of the VTA increases aggression -> turning on reward system -> increase aggression (ChR2+ neurons).