Neurobiology of Fear #4

Neurobiology of Anxiety disorders

• Cued and contextual fear conditioning are used as animal models for studying the neurobiological basis for human disorders such as:
• Understanding the neural circuits that drive fear and anxiety may allow us to develop new treatments for these disorders
• We would like to know: how can fear be inhibited or suppressed?

++ understanding these behaviors are very important for developing new treatment for anxiety disorders in humans.

++ posttraumatic stress shares a lot in common of with tone and context conditioing in rats. Soldier goes to war (loud noise predict bad thing - associate loud noises to danger- after back from war, loud noises still provode aversive reaction)

++ treatment -- fear can be inhibited or suppressed?

 

Fear Extinction

• Repeated presentation of the CS without the US can cause extinction of fear conditioining (results shown below for two groups of rats)
• Extinguished responses to a CS can return in one of three ways:

++ more time we pair, animal freeze more, / playing tone without shock, animals learn new association that the tone no longer predicts shock

++ PTSD - exposed to the thing provokes strong reaction in a control setting -> less strong aversive reaction

++ not forgetting, they learn new association

++ even with small shock, completely recover the fear to the tone

++ therapist office, exposed to dog related to stimuli, -> see a dog in another environment -> recover fear

 

Medial Prefrontal Cortex (mPFC)

• PL = prelimbic or dorsomedial PFC (dmPFC) (more freezing)
• IL = infralimbic or ventromedial PFC (vmPFC) (less freezing)

++ in extinction learning, medial prefrontal cortex is very important to change. Dorsal part of prefrontal cortex or prelimbic cortex is more importnat for decreasing extinction of learning (increasing freezing), and ventral part of prefrontal cortex or infralimbic cortex is important for excellerating that extinction of learning (decreasing freezing)

++ activation of ventral part, you will get more effective fear extinction learning

• It has found that electrical stimulation of PL during extinction enhances conditioned freezing (and impairs extinction of freezing), whereas electrical stimulation of IL during extinction impairs conditioned freezing

++ they expose the rat to tone with absence of the shock (with or w/o stimulation of dorsal or ventral prefrontal cortex ->

++ electrical stimulation to prelimbic(dorsal) -> more freezing  || ventral part -> less freezing

 

How does IL inhibit freezing behavior?

• Evidence suggests that IL inhibits fear by sending excitatory projections to basomedial amygdala, which then excites inhibitory neurons that inhibit Ce
• INHIBITING FEAR -why should we care? - a dominant theory of posttraumatic stress disorder (PTSD) proposes that repeated exposure to fear and trauma leads to a chronic condition in which patients suffer from too MUCH activation of the amygdala, and to LITTLE activation of IL. Much current research into treatments for PTSD is focused upon understanding this circuitry better
• When an anterograde tracer molecule (green) was injected into PL (or dmPFC), very few axon terminals were labeled in the basomedial amygdala (BMA). But many axons were labelled when the tracer was injected into IL (or vmPFC)

++ prelimbic cortex stimulate the Basal nucleus amygdala which causes more excitation on the Ce which provokes freezing. Conversly, infralimbic cortex projects to Basomedial nucleus amygdala which is also called accessory B, and this nucleus activates inhibitory cells in the amygdala called "intercl inhibitory cells" and this inhibits the central amygdala which would decrease freezing

++ brain regions slightly adjacent each other can have opposite functions

 

 

Inhibition of freezing by optical stimulation of BMA

• When BMA neurons were infected with ChR2, stimulating these neurons with blue light suppressed conditioned freezing

++ if you optogenetially activate the basomedial amygdala directly with blue light, then after learning of the fear tone conditioning, you see that the animal freeze much less to the tone (if the tone pair with blue light stimulation in the basomedial amygdala)

++ which nuclei in the amygdala is important for which part of the behavior --> eventually targeted pharmachological therapy.

 

 

The amygdala also controls innate anxiety

• Innate anxiety can be measured in rodents by avoidance of open spaces and bright lights
• The central lateral amygdala (CeL) inhibits the anxiety and fear inducing central medial amygdala (CeM)
• Optogenetic activation of the excitatory projection from basolateral amygdala (BLA) to CeL increases exploration of open spaces, indicating a reduction in anxiety
• Optogenetic activation of the entire BLA increases open space avoidance, probably because of activation of BLA projections to the anxiety-inducing CeM

++ amygdala is not only important for fear conditioning but also important for anxiety related behavior. Anxiety is kind of reaction to low level threat (ex., rat prefer closed space)

++ open field task. If you let a mouse run around, it run around in the periphery not in the center. Bc exposed to predator in center region. But if you activate the optogenetically projection from basolateral amygdala (BLA) to CeL, you will get mouse explore the center more(less afraid of going to center part)

++ central nucleus amygdala can be divided into two regions. (central medial region -output to periaqueductul- cause more freezing) (central lateral nucleus - inhibit central medial nucleus)

++ more activation of central lateral nucleus lead to less central medial output which create less fear anxiety behaviors

++ stimulate optogenetically connection from the basolateral amygdala to this inhibitory central lateral nucleus which decrease defensive behavior (more going to center)