case 3 - psychosis Flashcards
mesolimbic DA functions
Dopamine (DA) modulates circuit reactivity based on environmental stimuli and prior experience and thus plays a central role in functions including reward processing, reinforcement, and habit formation.
Midbrain DA neurons have also been shown to respond to novel or aversive stimuli in the absence of reward and it has been proposed that DA signaling may more generally influence sensory processing, such as weighting the salience or certainty of perceived stimuli.
DA dysfunction in SZ
Dopamine dysfunction in schizophrenia
* Increased baseline levels of synaptic DA in striatum
* Elevated striatal DA synthesis capacity
* Increased DA function likely most clearly signals active psychosis
* Elevation in DA is limited to striatal projections
* Mesocortical projections, particularly to the dorsolateral PFC, display reduced DA release compared to healthy controls, which may contribute to impaired prefrontal-dependent cognitive processes
activity states of midbrain (VTA) DA neurons
DA neurons exhibit two patterns of activity, known as tonic and phasic states, that have different functional implications and are regulated by distinct afferent systems.
* DA neurons in tonic state show spontaneous activity through the generation of a pacemaker conductance –> low extrasynaptic DA which is not controlled by DATs
* When exposed to a behaviorally salient stimuli, such as a potential threat or reward, tonic state DA neurons may shift to rapid, phasic burst firing –> high intrasynaptic DA which is controlled by DATs
* NOT ALL DA neurons are in tonic state in the absence of a salient stimulus; some do not show spontaneous activity (hyperpolarized), and are thus unable to shift to burst firing upon stimulation
* the vHipp-nucleus accumbens-ventral pallidum (vHipp-NAc-VP) circuit allows the baseline level of responsivity of the DA system, which is dependent on population activity, to be adjusted based on the context in which the stimuli are presented.
VHipp in psychosis
- Deficits in the structure (atrophy) and function of the hippocampus are consistently observed in imaging and post mortem studies of schizophrenia patients
- Imaging studies show that the anterior hippocampus, which is homologous to the limbic vHipp in rodents, is hyperactive in individuals with schizophrenia
- Multiple lines of evidence have suggested that the hippocampal hypermetabolism is due to reduced parvalbumin (PV)+ GABA interneuron regulation of pyramidal neuron activity, secondary to excitotoxic degeneration of PV+ interneurons
central regulation of DA system
- mPFC
- Thalamic nuclei
- medial septum
Overall, these findings suggest that a loss of top-down prefrontal regulation via disruption of corticothalamic communication, as has been observed in schizophrenia, could contribute to hippocampal overdrive and, consequently, to the hyperdopaminergic state characteristic of the disorder.
mPFC regulation of DA system
- Contrary to the increased presynaptic striatal DA synthesis and release, it has been found that DA transmission is decreased in the PFC of schizophrenia patients
- This cortical hypodopaminergic state is thought to be associated with impairments in cognitive and executive function in schizophrenia
- Two major mPFC subdivisions, the infralimbic (ilPFC) and the prelimbic (plPFC) cortices, send direct projections to the VTA as well as to other regions linked with control of the midbrain DA system, such as the NAc
o Activation of the ilPFC decreased VTA DA neuron population activity and vice versa
o ilPFC activation also stimulates the basolateral amygdala (BLA):
Activation of the BLA has been shown to decrease DA neuron population activity in the rat VTA, which is proposed to be due to a glutamatergic projection to the ventral pallidum
o plPFC inactivation decreased VTA DA neuron population activity (not vice versa)
- The mPFC does not directly project to the vHipp
Thalamic nuclei regulation of DA system
- The nucleus reuniens is bidirectionally connected to the hippocampus and PFC
o Activation of the nucleus reuniens increases DA neuron population activity in the VTA via its projection to the vHipp
o The increased VTA DA neuron population activity upon inactivation of the ilPFC may occur via ilPFC projection to the nucleus reuniens (via TRN see figure)
o Convergent glutamatergic inputs from the vHipp and paraventricular nucleus of the thalamus to the NAc work in concert to regulate VTA DA neuron activity
Mseptal control of DA system
- The medial septum sends dense cholinergic and GABAergic projections to several hippocampal regions, including the vHipp
o The GABAergic projections from the medial septum synapse primarily on PV+ interneurons in the hippocampus
o The cholinergic projections provide slow depolarization of their target pyramidal neurons - Medial septum activation increases VTA DA neuron population activity and inhibits the substantia nigra in the normal rat
o This is reversed in the MAM schizophrenia rodent model
Stress and VTA neurons
- The vHipp expresses a high amount of GRs
o While an elevation in GCs is essential to respond to perceived threat, chronic elevation can result in impaired function and hippocampal atrophy
o Prolonged stressors can lead to dendritic shrinkage and neuronal loss in the hippocampus, including a loss of PV+ interneurons - Extreme stress, or a failure of the PFC to mitigate the impact of stress, could lead to loss of PV+ interneurons in the hippocampus in late adolescence or early adulthood
Why is the prepubertal period unique in its susceptibility to stress-induced PV interneuron damage? Studies have shown that the PV interneurons play a unique role in neuronal systems development. -
- Early in life, PV neurons exhibit a substantial amount of plasticity, with glutamatergic synapses forming and being removed as the organism learns to deal with environmental contingencies.
- However, this plasticity comes at a price, in that the PV neurons are highly vulnerable to stressors at this time point.
–> Thus, oxidative stress, glutamate drive, high-frequency firing, could all contribute to pathology and cell death.
However, after puberty the PV neurons develop a perineuronal net that protects them from damag
salience attribution
By adjusting the number of DA neurons active, the vHipp can adjust the gain of the DA signal to appropriately fit the context. Therefore, in the dangerous environment, the vHipp causes a high level of DA population activity, such that a noise will activate a higher proportion of DA neurons, leading to greater phasic DA release that can drive a rapid orientation toward the stimulus to decide on an appropriate response.
aberrant salience attribution
aberrations in salience processing are where attention and action selection are redirected to irrelevant stimuli, internal or external, or directed diffusely, leading to sensory overload.
–> The delusions that characterize psychosis emerge out of this context
VTA neurons functional heterogeneousity
distinct subgroups may code for either salience or reward prediction errors –> more medial dopamine neurons innervate more medial target regions
- Dorsolateral striatum elevated DA signaling may be of special importance since the dorsolateral striatum is functionally linked to associative cortical regions such as the dorsolateral prefrontal cortex and is thought to be involved in the attentional salience of stimuli, suggesting that this may be important in the development of psychosis
Increased dopaminergic tonic transmission is likely to mainly affect high affinity D2/3 receptors, which are the target of antipsychotics, whereas increased phasic transmission may be more likely to affect low affinity D1 receptors –> different cells and microstructures are involved
Bursting gate
The LDTg input provides the permissive ‘gate’ that enables dopamine neurons to respond to a glutamatergic input with a transition to this behaviorally relevant phasic burst-firing mode. There are several potential sources for this glutamatergic input, including the prefrontal cortex (PFC), pedunculopontine tegmentum (PPTg) and lateral preoptic–rostral hypothalamic area.
PPTg
The PPTg is a glutamatergic–cholinergic region driven by limbic afferents, including the PFC and extended amygdala, and activated by auditory, visual and somatosensory stimuli. Moreover, the PPTg has been demonstrated to directly regulate burst firing of dopaminergic neurons in the VTA. Thus, activation of the PPTg triggers a transition to burst firing in dopamine neurons of the VTA which projects to the NAc and associative striatum. The PPTg is, therefore, positioned to serve as a site of convergence, whereby a variety of sensory inputs can modulate burst firing of dopamine neurons.
> > > By contrast, in the substantia nigra the glutamatergic input from the subthalamic nucleus seems to be more relevant to engaging burst firing
Tonic vs phasic firing - spatially
fast-acting phasic dopamine transmission is expected to modulate the activity of only a subgroup of medium spiny neurons in the NAc. Thus, this mode of dopamine signaling might have a particularly important role during the early stages of reward-related associative learning, altering synaptic strengths of selected limbic striatal inputs to particular ensembles of NAc neurons.
By contrast, slower changes in the tonic levels of dopamine, regulated by the overall activity of the population of dopamine neurons, are more spatially distributed, modulating the activity of a large number of neurons in the ventral striatum, in addition to modulating presynaptic glutamatergic inputs from different limbic and cortical regions.
