Unit IV week 1 Flashcards
Major Depressive Episode criteria
SIG-E-CAPS
requires depressed mood or diminished interest (anhedonia) and at least 5/9 criteria for at least 2 weeks, causing serious impairment in functioning
SIG-E-CAPS
Major Depressive Episode criteria
Sleep - too much or too little Interest - decreased Guilt - increased Energy - decreased Concentration - decreased Appetite - decreased or increased Psychomotor agitation/retardation Suicidal ideation
Mania and Hypomania criteria
DIGFAST
- Distractibility - attention too easily drawn to unimportant or irrelevant external stimuli
- Irritable/elevated/expansive mood
- Grandiosity (inflated self esteem)
- Flight of ideas, subjective experience of racing thoughts
-Activities
High potential for painful consequences (buying, sexual)
Goal directed or psychomotor agitation
- Sleep - decreased need for sleep
- Talkativeness
Hypomania
4 days, not marked impairment in functioning, not psychotic
Bipolar I
patients must have had mania, but also may have hypomania and major depressive episodes
Bipolar II
patients must have had hypomania and MDE
Major depressive disorder
has had MDE, but never hypomania or mania
Cyclothymia
hypomania and subsyndromal depression
Dysthymia
subsyndromal depression
Schizophrenia
> 6 months
Delusions: fixed belief not amenable to change in light of conflicting evidence
Hallucinations: perception like experiences that occur without an external stimulus
Disorganized thinking or speech: frequent derailment or incoherence
Grossly disorganized or abnormal motor behavior (including catatonia)
Negative symptoms: alogia (poverty of speech), affective flattening (decreased expression of emotions, lack of expressive hand gestures), asociality (few friends)
Schizoaffective disorder
if psychotic symptoms are present throughout, but mood symptoms are present majority of time = MDE + psychotic episode
Schizophreniform disorder
> 1 month, but less than 6 months
Pharmacotherapy for Psychosis (2)
1) Typical neuroleptics (first gen antipsychotics)
- Affect dopamine pathway - D2 antagonism
2) Atypical neuroleptics (second gen antipsychotics)
Effect serotonergic pathways
Diencephalon = _________ + ___________
Thalamus (dorsal) + Hypothalamus (ventral)
Hypothalamus
homeostasis, intimately associated with pituitary, amygdala, preoptic area, nucleus of the solitary tract, autonomic preganglionic motor nuclei
Thalamus
gateway to cortex
Each area of cortex has corresponding thalamic relay nucleus
Thalamocortical connections main features (3)
All connections are reciprocal
Right thalamus deals with contralateral side of body
Acts as gateway to cortex - EXCEPT for olfactory system (olfactory cortex → orbitofrontal cortex)
Relay nuclei of thalamus
1) Anterior nucleus → Cortex (cingulate gyrus) (Limbic, emotions)
2) VA/VL nucleus → motor cortex (somatosensory)
3) LGN (visual)
4) MGN: inferior brachium → MGN → auditory cortex (auditory)
Somatosensory nuclei of thalamus (2)
Face sensation via trigeminal pathway → VPM
Body sensation via medial lemniscus and spinothalamic tract → VPL
Association nuclei of thalamus (2)
Pulvinar nucleus → parieto-occipital association cortex (visual)
Dorsomedian nucleus → frontal association cortex (frontal cortex)
Two “other” nuclei of thalamus (2)
Centromedian nucleus (motor)
Reticular nucleus - sheet of cells on lateral surface, primarily inhibitory interneuron with connections to all other nuclei)
3 Major circuit systems of thalamus
1) Thalamocortical
2) Lentiform Nucleus/Basal Ganglia
3) Limbic System
Anterior limb of the internal capsule
origin:
destination:
runs where?
runs between caudate (medial) and lentiform nucleus (putamen/globus pallidus) (lateral)
Origin: anterior nucleus of thalamus, DM nucleus
Destination: cingulate gyrus and prefrontal cortex
Genu of internal capsule
flexure of internal capsule
Contains fibers of corticobulbar tract
Posterior limb of internal capsule
runs where?
contains fibers from where?
origin and destination?
between thalamus (medial) and lentiform nucleus (putamen/globus pallidus) (lateral)
Contains corticospinal and ascending thalamocortical fibers
Origin: motor cortex, VPL/VPM
Destination: spinal cord and brainstem, and postcentral gyrus
Retrolenticular limb of internal capsule
origin
destination
Origin: Pulvinar and LGN
Destination: Parietal association cortex and visual cortex
Sublenticular limb of internal capsule
origin
destination
Origin: LGN and MGN
Destination: Visual cortex and auditory cortex
Broadmann’s areas:
1-3 = ? 4 = ? 17 = ? 41 = ?
1-3 = Primary sensory 4 = Primary motor 17 = Primary visual 41 = Primary auditory
EEG
measures small field potentials at surface of skin overlaying skull
Voltages measured in EEG generated by neurons near surface - reflect synchronous synaptic input to cortical neurons
Thalamic Relay Neurons
Receive input from a sensory system, relays info to cortex via excitatory glutamatergic synapses onto pyramidal cortical neurons with soma in layer IV of cortex
Thalamic relay neurons do what when you are awake?
Awake → little inhibitory input to thalamic relay neurons, membrane potential rests at -55mV → fire series of APs at high frequency
Thalamic relay neurons do what when you are asleep?
Asleep → Thalamic reticular neurons release GABA and inhibit relay neurons → membrane potential at -85mV → fire bursts of APs on top of a Ca2+ spike
Ca2+ spikes during sleep in thalamic relay neurons are generated by what?
- Ca2+ spike happens with 3Hz frequency generated by T-Type Ca2+ channel
- Channel inactivated by depolarization
- When relay neurons inhibited by thalamic reticular cells, inactivation gate opens, and T-Type Ca2 channel generates Ca2+ spikes at 3Hz frequency
- Fast APs ride on top of this Ca2+ spike
Thalamic relay neurons send axons to _________ which then…
Relay neurons then send axons to cortical pyramidal cells → pyramidal cell fires at delta frequency → Slow EEG recording
EEG and slow wave sleep
Slow wave sleep stage is characterized by a pattern of slow wave oscillation of EEG at frequency of 3Hz (delta wave)
Ascending control of thalamocortical circuits comes from the _________ via ________, ________, and ________ neurons
Brain stem
ascending cholinergic, noradrenergic, and serotonergic neurons
When you are asleep and are stimulated by ______ from ________ neurons in the ___________ system you wake up and interrupt slow waves
ACh
Cholinergic neurons
Reticular activating system
__________ neurons from ___________ –> release noradrenaline in thalamus
activated during ____________
noradrenergic neurons
from locus coerulus
activated during fight/flight response
_________ neurons from __________ –> release serotonin in thalamus
serotonergic neurons from raphe nuclei
Absence Epilepsy
when child has sudden staring spells
Child stops what he/she is doing, stares for a few seconds, and then resume
EEG pattern similar to slow wave sleep (d waves of 3Hz)
Simple absence seizures
Impairment of consciousness
Minimal motor activity (eyelid fluttering, blinking)
Lasts 5-15s, average of 100 seizures a day
Complex absence seizures (5)
Impairment of consciousness
Prominent motor activity (myoclonic jerks, automatism, atonic)
More common than simple
Automatisms: persistence of action, mumbling, nonpurposeful movements
Autonomic features: pallor, change in HR/RR, mydriasis, micturition
Mice without T-type Ca2+ channel and anticonvulsants that block T-type Ca2+ channels
what impact?
Mice without T-type Ca2+ channel cannot be induced to have these seizures
anticonvulsants that block T-type Ca2+ channels are effective against absence epilepsy
Generalized seizure
seizure activity in entire brain
May start in a focal area, but then goes generalized
Tonic (rigid)
Clonic (on/off)
Childhood absence epilepsy
Onset 4-8 years, remission in 80% by adulthood
Juvenile absence epilepsy
onset 4-30 years
Less frequent absence seizures, duration may be longer, some preserved awareness
Juvenile myoclonic epilepsy
infrequent absence seizures
GTC/myoclonic seizures (surrounding sleep) are predominant features
No remission, but may be responsive to treatment
EEG results in:
Typical absence seizure
normal background organization and frequencies
Ictal discharges:
- Abrupt onset and offset
- Generalized 3Hz spike and wave
- Frontal maximum
Spikes may become fragmented and irregular during sleep
EEG results in:
Atypical absence seizures
often abnormal background with slowing and disorganization
Ictal discharges at 2-2.5Hz, more irregular
Treatment of epilepsy (2 drugs)
Valproic Acid
Ethosuximide - acts on T-type Ca current
Declarative Memory
ability to recollect events or facts that have a specific temporal and spatial context
HIPPOCAMPUS important for formation of declarative memory
Procedural Memory
ability to learn new motor skills
Cerebellum, striatum and frontal cortex important for formation of procedural memory
Short-Term Memory
lasts for fractions of a second to seconds
Occurs in SENSORY CORTEX
Working Memory
lasts seconds to minutes
Located in FRONTAL LOBES where executive function (ability to react in morally appropriate way) is also located
Long-Term Memory
lasts for days and years
Stored in CORTEX
Long term memory storage is in _______________
evidence?
NEOCORTEX
fMRI and lesion studies indicate long term-term declarative memory is stored in neocortex
Patient HM
Had bilateral symmetric removal of half of rostrocaudal extend of hippocampus, adjacent entorhinal cortex, and amygdaloid complex
Produced severe anterograde amnesia
Capable of recollecting memories before surgery, but cannot recollect facts after surgery
Deficit in declarative memory and semantic knowledge
Procedural memory was NOT affected
Associative memory
learning to associate several cues with a particular fact or object
Long Term Potentiation and Associative Memory
Input 1 = axons representing large number of cues required before you learn
during learning what happens?
During learning, you stimulate postsynaptic cell vigorously and repeatedly through all axons of input 1 → synapse strengthens (elicit depolarization of postsynaptic neuron when a smaller subset of axons in input 1 is stimulated)
EX) permit recall of movie title with four cues instead of eight
Potentiation occurs ONLY when…
Potentiation occurs ONLY when reinforcement and relevant sensory stimulus are turned on at the SAME time
What happens when input 2 (axons that have not undergone LTP) are stimulated?
stimulating subset of those axons would not result in postsynaptic depolarization ensuring you respond correctly
Mice experiment: mice learn to use visual cues provided by objects around pool to locate hidden platform, and can still do this when some objects removed
what happens when area ______ of hippocampus of mice is damaged
CA3
mice have harder time finding submersed platform with reduced number of cue
LTP in _____ area important for associative memory
CA3
Dentate gyrus
one layer of neuron cell bodies arranged in spiral semicircle
Ammon’s horn
larger spiral semicircle of neuronal cell bodies surrounding dentate gyrus
CA3 neurons and CA1 neurons of Ammon’s horn region are involved in long term potentiation, and serve basis for memory consolidation
Input to hippocampus from _______ via ______ path. This input synapses on ________ and ________ neurons on Ammon’s horn
From entorhinal cortex via perforant path
Perforant path axons synapse on dentate gyrus and CA3 neurons in Ammon’s horn
Entorhinal cortex gets widely distributed input from neocortex
Input to hippocampus (3)
1) Entorhinal cortex
2) Moss fibers
3) Schaeffer collateral axons
Mossy fibers
cells from dentate gyrus that synapse on the CA1 neurons
Schaeffer collateral axons
originate from CA3 neurons and synapse onto CA1 neuron
Hippocampus and LTP:
Two characteristics
1) Only synapses that are being stimulated during tetanus undergo LTP
2) LTP only takes place when titanic burst large enough to cause cell depolarization in postsynaptic neuron
**The only synapses whose effectiveness is increased are those that are being stimulated by release of NTs (glutamate) and are simultaneously being depolarized postsynaptically as a result of depolarization elicited by large summated input elicited by the tetanus
Molecular basis for LTP
1) NMDA receptor requires glutamate binding and depolarization of postsynaptic membrane to remove Mg2+ and allow Ca2+ to flow into cell
2) Ca2+ IN stimulates Calmodulin → stimulate calcium/calmodulin dependent protein kinase II (CAMKII)
3) CAMKII phosphorylates itself causing prolonged activation of CAMKII
EPSP size in LTP is increased how? (2)
→ increases EPSP size by:
1) incorporating AMPA receptors in postsynaptic membrane
2) phosphorylation of AMPA receptors making them more responsive to glutamate → STRUCTURAL CHANGE
Synapse formation in learning and memory
Synapses are NOT static: synapse formation and destruction can contribute significantly to learning
Adult neurogenesis in learning and memory
Adult Neurogenesis:
Occurs in olfactory bulb - involved in olfactory learning
Hippocampus - involved in declarative learning
Cerebellum - involved in procedural learning
Alzheimer’s Disease pathophysiology
Early stage: affects synaptic transmission in limbic and association cortices
Loss of ability to encode new declarative memories in an individual with otherwise normal intelligence, motor, and sensory functions
APP, when cleaved by B and y secretases → neurotoxic AB protein
→ AB proteins assemble and cause cognitive impairment through loss of synapses and subsequent neurodegeneration
Kluver-Bucy Syndrome
removal of amygdala
- Alteration in feeding
- Attempting to make with individuals of other species
- Lack of concern of previously feared objects
Conditioned fear
Sound conditioned to shock
Sound = auditory system, Conditioned stimulus
→ thalamus → auditory cortex and amygdala (lateral nucleus of amygdala)
Shock = pain system, unconditioned stimulus
→ somatosensory thalamus (VPL) → somatosensory cortex and amygdala
*Amygdala involved in this learning
Emotional limbic system (6 structures)
1) amygdala
2) cingulate gyrus
3) mediodorsal nucleus of thalamus
4) ventral basal ganglia (ventral caudate and putamen)
5) insular cortex
6) hypothalamus
Limbic System and Amygdala in Emotion
Emotions expressed by autonomic visceral (hypothalamus) and somatic motor actions (reticular formation in brainstem)
-role in conditioned fear learning
Conditioned flavor aversion
Two cues separate in time (food flavor and malaise) → change neural circuit resulting in learned aversion for food
EX) Cancer patient receives taste and olfactory stimulation from eating food, and gets sick within ½ hour → avoid food in future
Happens with single episode of malaise and can last for years
Where does conditioned flavor aversion?
INSULAR CORTEX
Mechanism of conditioned flavor aversion
Muscarinic receptors in insular cortex are essential for CFA acquisition
Muscarinic stimulation of neurons in insular cortex → activate kinases and phosphorylate NMDA receptors → affects response to stimulation from fibers coming from amygdala
Stimulation through amygdala → associative learning that causes aversion to food that was paired with malaise
Limbic System is responsible for what 4 main functions
HOME
Homeostasis
Olfaction
Memory
Emotion
Papez circuit is made up of what 4 components
1) Hypothalamus with mamillary bodies
2) Anterior thalamic nucleus
3) Cingulate gyrus
4) Hippocampus
Papez circuit
cingulate gyrus → hippocampus → Hippocampus projects to hypothalamus (via fornix) → anterior thalamic nuclei → cortex
proposed as anatomic basis for central functions of emotion and peripheral expression
Theory of emotion: amygdala responsible for what?
Amygdala: responsible for formation and storage of memories associated with emotional event
Amygdala gets input from where?
Highly processed visual information, piriform/olfactory input, and other visceral sensory inputs
Parts of Amygdala (3)
1) Centromedial Amygdala = output
2) Basolateral Amygdala (BLA) = input
3) Intercalated cells = islands of cells between two structures
- Important in fear extinction
Fear conditioning: pair auditory stimuli (CS) with shock (US)
Sensory stimuli reach ___________ –> ?
Sensory stimuli reach basolateral nuclei of amygdala (BLA) → form associations with memories of stimuli
auditory stimuli undergoes LTP for predictions of adverse events and stimuli
The basolateral amygdala (BLA) elicits fear behavior through connections with…(2)
BLA elicits fear behavior through connections with central nucleus of amygdala (CEA) and related bed of nuclei of stria terminalis (BNST)
What are fear behaviors?
Fear behavior = freezing, tachycardia, increased respiration, stress-hormone release
Central nucleus of amygdala mediates what?
expression of emotional responses
Lesion of amygdala does what to fear and positive conditioning?
Lesion of amygdala prevents acquisition of fear and positive conditioning
Dopaminergic neurons from VTA project to ________ in _________
stimulation of this area does what?
project to nucleus accumbens in ventral striatum
Stimulation of nucleus accumbens is highly reinforcing
Excessive dopamine in this circuit excessively reinforces networks that were active during behavior that produced the dopamine surge
VTA also projects to ______ and _______ creating what two pathways?
projects to amygdala, and VMPFC = mesolimbic and mesocortical dopaminergic pathways
Iowa Gambling Task and the Ventromedial PFC
Iowa Gambling Task: lesions to VMPFC means patients tend to continue to draw from “bad” decks even though they know they are losing
Healthy participants show anticipatory emotional response (stress response) preceding explicit knowledge of correct strategy
Implications of Iowa gambling task findings in patients with VMPFC lesion
VMPFC injured patients never develop anticipatory physiologic reaction to impending punishment
BUT had intact stress responses to receipt of actual rewards and punishments
→ VMPFC important for predictions of consequences but not necessary for registering actual consequences
Implies VMPFC role in suppression of behaviors felt to be excessively risky, especially in context of social function
Impairment in ability to estimate risk/reward associated with certain behaviors, and ability to select behaviors based on risk/reward calculations
What happens to your decision making when you damage your VMPFC?
VMPFC damage → engage in behaviors that are detrimental to well-being
What happens in the Iowa Gambling task when you have a lesion in your amygdala
Amygdala damage → similar performance on Iowa gambling task as VMPFC, but these patients ALSO failed to show conductance responses to actual receipt of rewards and punishments
→ amygdala triggers emotional bodily states in response to rewards and punishments associated with specific behaviors or stimuli
→ VMPFC represents relations between inputs and outputs that the amygdala has constructed
-A set of predictions of likely consequence of different actions
Amygdala
links aversive and appetitive stimuli with physiologic responses, action patterns, perceptions, and predictions
critical integrative structure projecting to VTA and nucleus accumbens
Insula
constitutes primary olfactory, gustatory, and visceral sensory cortex
Links between insula, VMPFC, and amygdala relate these senses to emotion
VMPFC and ventral striatum
are (Respectively) critical for generating and reinforcing predictions about risks and rewards associated with actions
VTA
Reward and punishment salience) signals contribute to synaptic plasticity and associative learning in amygdala, ventral striatum and VMPFC
midbrain structure with dopaminergic cells innervating all the reward pathway structures
Hippocampus
memory circuit involved in mediating associations between biologic stimuli (or drugs of abuse) and environmental cues
Prefrontal cortex and drugs of abuse
critical for executive function in providing control over impulses from destructive behavior
Impairment following chronic drug abuse important mediator in loss of control over drug intake (Addiction)
Function of the reward pathway
mediate pleasure (reward) and the strengthening of behaviors (reinforcement associated with natural reinforces (food, water, sex)
Produces motivational states
Modulation of physiological and behavioral responses ensuring survival and reproduction
Reward
something brain interprets as intrinsically positive
Reinforcing stimulus
increases probability of behaviors paired with it will be repeated - not all reinforcers are rewarding (can reinforce avoidance behaviors)
Mesolimbic system
Stimulation of VTA neurons by natural reinforcers → dopamine release in nucleus accumbens
dopamine pathway, final common pathway of reinforcement and reward
Dopamine affects motivation and attention to a salient stimuli
Mesolimbic system and drugs of abuse
ALL drugs with dependence liability share this final common pathway of increasing synaptic dopamine levels in nucleus accumbens
More intense/direct effect drug has on dopamine neurons, the greater addiction potential
Reactive reward system is made up of what 3 structures?
VTA (dopamine cell bodies) + nucleus accumbens (where DA neurons project) + amygdala (connects VTA and NA)
Reactive reward system:
amygdala connects to _________ as a relevance detector
Amygdala connects to _________ to signal what?
Learning conditioned in amygdala
Amygdala → connects back to VTA as a relevance detector (for anything relevant to previous drug abuse experience)
Amygdala → connects to nucleus accumbens to signal emotional memories triggered by internal or external cues
→ initiate impulsive-automatic-obligatory actions to find/take more drugs
Reactive reward system and drug abuse
**drug addiction produces changes whereby the “reactive reward” system hijacks the normal reward circuitry
repeated exposure to drugs of abuse results in pathologic “learning” to trigger drug-seeking behaviors when presented with internal (craving, withdrawal) or external (environmental associations) cues
Function of reactive reward system
signal immediate prospect of pleasure or pain and provides motivational and behavioral drive to achieve that pleasure or avoid that pain
Reflective reward system connects _______ to ______ including projections to what 3 areas for what purpose?
connects PFC to nucleus accumbens
Orbitofrontal projections → regulate impulses
Dorsolateral PFC → analysis of situation
VMPFC → integration of impulsiveness and cognitive flexibility with its regulation of emotions
Reflective reward system and drugs of abuse
balance between reactive reward drives and reflective reward decisions determine whether output of reward circuitry converted into short term rewards (drug seeking) or long term
Compulsive drug use: Repetitive drug-induced rewarding experiences → what 4 things
1) Alter reward circuits so drug ingestion and cues that merely predict pleasure will activate MESOLIMBIC DOPAMINE RELEASE
2) Amygdala learns that drug causes pleasure and drug cues with pleasure
3) Drug cues → DOPAMINE RELEASE in NAc → GABA output from NAc → thalamus → prefrontal cortex
4) Absence of activity in reflective reward system → drug seeking behavior initiated
Highest addictive potential for drugs of abuse with:
Modes of administration?
Rate of onset?
IV and inhalational routes are associated with most rapid rise in brain levels of drug and greater likelihood to produce addiction
Rate of onset: abuse liability increased with faster onset of action
Highest addictive potential for drugs of abuse with:
Termination effects?
drugs with shortest half lives tend to have higher abuse liabilities
Withdrawal effects more severe for drugs with short half lives → continued drug administration just to prevent withdrawal
Psychosis
characterized by derangement of personality and loss of contact with external reality - primary disorder in thinking
Four components of psychosis
1) Hear voices and have other sensations that are not real = Hallucinations
2) Believe they are influenced by unseen forces around them = Paranoid Delusions
3) Being tormented, harmed, followed, tricked, or spied on = Persecutory Delusions
4) Have other disorders in thought, typically idiosyncratic associations that are evidenced in disorganized speech or writing = formal thought disorder
Schizophrenia
inability to discern what is real and not real, to think clearly, have normal emotional responses, and act normally in social situations
Schizophrenia positive and negative symptoms
Positive Symptoms:
- Hallucinations, generally auditory
- Delusions, belief that external forces conspiring against him/her
Negative symptoms (deficit symptoms):
- Inability to pay attention, loss of sense of pleasure, loss of will or drive, disorganized or impoverished thoughts and speech, flattened affect, social withdrawal
- Cognitive deficits
Diagnostic criteria for schizophrenia
- at least 2 symptoms
- Social/occupational dysfunction in work, interpersonal relationships, or self care
- Duration of symptoms for at least 6 months
- Illness not due to a medication, medical condition, or substance abuse
- Illness not part of autism or developmental disorder
(High likelihood of substance abuse)
Prevalence and age of onset of Schizophrenia
Prevalence: 1% of world population, 2.4 million people
Age of onset: late adolescence, early adulthood, continue throughout life
-Earlier behavioral dysfunction, primarily social and learning difficulties
Drugs that can resemble schizophrenia (5)
1) Dopamine agonism (cocaine, amphetamine)
2) Norepinephrine agonism (cocaine, amphetamine)
3) Serotonin agonism (hallucinogens, LSD)
4) NMDA antagonism (dissociative anesthetics, phencyclidine, ketamine)
5) Acetylcholine antagonism (anticholinergics, atropine)
Dopamine theory of schizophrenia
1) HYPERactivity of mesolimbic system –> POSITIVE SYMPTOMS
2) HYPOactivity of mesocortical system –> NEGATIVE symptoms
Mesolimbic system
dopamine neurons from VTA release dopamine to nucleus accumbens → regulate reward pathways and emotional processes
- integration of sensory input and motor responses with affective or emotional data
- Antipsychotic agents (via D2 block) are most effective in reducing positive symptoms (delusions, hallucinations, disordered cognition)
Mesocortical system
dopamine neurons from VTA and substantia nigra release dopamine to prefrontal cortex → regulate areas involved in cognitive processing and motor control
DLPFC and VMPFC involved in communication and social abilities
Hypoactivity due to cell loss in PFC → negative symptoms (poverty of speech, anhedonia, lack of motivation, social isolation)
Glutamate Model of schizophrenia
glutaminergic hypoactivity → psychosis
Mechanism behind glutamate model of schizophrenia
Glutamate binds dopamine neurons → produce regional hyperactivity and hypoactivity in dopamine neuron release
**Increased cortical output due to loss of cortical GABA inhibition→ increase mesolimbic DA release → Positive symptoms
**Increased cortical output due to loss of cortical NMDA-glu neurons→ loss of cortical GABA inhibition → increased activity of cortical glutamate neurons → decreased mesocortical DA release → Negative symptoms
GABAergic model of schizophrenia
reduced parvalbumin positive interneurons in laminar III of prefrontal cortex
