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Improper activation of D1 and D2 receptors leads to excess noise in prefrontal cortex.

Avery MC, Krichmar JL - Front Comput Neurosci (2015)

Bottom Line: We developed a model that takes into account the known receptor distributions of D1 and D2 receptors, the changes these receptors have on neuron response properties, as well as identified circuitry involved in working memory.Our model suggests that D1 receptor under-stimulation in supragranular layers gates internal noise into the PFC leading to cognitive symptoms as has been proposed in attention disorders, while D2 over-stimulation gates noise into the PFC by over-activation of cortico-striatal projecting neurons in infragranular layers.We apply this model in the context of a memory-guided saccade paradigm and show deficits similar to those observed in schizophrenic patients.

View Article: PubMed Central - PubMed

Affiliation: Systems Neurobiology Laboratory, Salk Institute for Biological Studies San Diego, CA, USA.

ABSTRACT
The dopaminergic system has been shown to control the amount of noise in the prefrontal cortex (PFC) and likely plays an important role in working memory and the pathophysiology of schizophrenia. We developed a model that takes into account the known receptor distributions of D1 and D2 receptors, the changes these receptors have on neuron response properties, as well as identified circuitry involved in working memory. Our model suggests that D1 receptor under-stimulation in supragranular layers gates internal noise into the PFC leading to cognitive symptoms as has been proposed in attention disorders, while D2 over-stimulation gates noise into the PFC by over-activation of cortico-striatal projecting neurons in infragranular layers. We apply this model in the context of a memory-guided saccade paradigm and show deficits similar to those observed in schizophrenic patients. We also show set-shifting impairments similar to those observed in rodents with D1 and D2 receptor manipulations. We discuss how the introduction of noise through changes in D1 and D2 receptor activation may account for many of the symptoms of schizophrenia depending on where this dysfunction occurs in the PFC.

No MeSH data available.


Related in: MedlinePlus

Negative symptoms in schizophrenia. (A) Chorley and Seth (2011) developed a model demonstrating how dopamine reward prediction error signals may be learned through the balance of excitatory and inhibitory projections. Excitatory signals from sensory areas fire phasically and drive dopamine neurons during the time of the stimulus (S) and the reward (R). Inhibitory signals from the striatum, on the other hand, also drive dopamine neurons, resulting in a constant firing rate during the time of the reward when the stimulus is predictive of the reward. (B) Our model suggests that the D2 state should affect striatum projections to dopamine neurons (top). That is, a high D2 state would increase the strength of inhibition on DA neurons, resulting in an overall lower firing rate for DA neurons and a dip in response at the time of the reward, despite the stimulus being predictive of the reward. Because PFC neurons that project to the striatum are driven by the corollary discharge (CD) in our model, an abnormal corollary discharge, as may be occurring in schizophrenic patients, could ultimately lead to abnormal DA responses (bottom).
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Figure 6: Negative symptoms in schizophrenia. (A) Chorley and Seth (2011) developed a model demonstrating how dopamine reward prediction error signals may be learned through the balance of excitatory and inhibitory projections. Excitatory signals from sensory areas fire phasically and drive dopamine neurons during the time of the stimulus (S) and the reward (R). Inhibitory signals from the striatum, on the other hand, also drive dopamine neurons, resulting in a constant firing rate during the time of the reward when the stimulus is predictive of the reward. (B) Our model suggests that the D2 state should affect striatum projections to dopamine neurons (top). That is, a high D2 state would increase the strength of inhibition on DA neurons, resulting in an overall lower firing rate for DA neurons and a dip in response at the time of the reward, despite the stimulus being predictive of the reward. Because PFC neurons that project to the striatum are driven by the corollary discharge (CD) in our model, an abnormal corollary discharge, as may be occurring in schizophrenic patients, could ultimately lead to abnormal DA responses (bottom).

Mentions: The idea that a low firing rate leads to negative symptoms (Loh et al., 2007) conflicts with the high firing rate in the low D1/high D2 state of our model and fMRI data showing an elevated BOLD signal in the PFC of schizophrenic patients (Manoach et al., 1999). We propose, instead, that negative symptoms arise due to noise in the reward prediction error signal. To build upon this idea, we briefly introduce a model (Chorley and Seth, 2011) that is able to account for how reward prediction error signals take shape in midbrain dopamine neurons. In their model, Chorley and Seth suggest that inhibitory signals from the striatum, which are driven by the PFC, must match excitatory signals from subthalamic nucleus for DA neurons to fire phasically for a stimulus predictive of a reward (Figure 6A). Our model predicts that D2 levels would affect the neurons in the PFC that project to the striatum and, therefore, could alter the reward prediction error signal of dopamine neurons. A high D2 state, then, would increase activity in the PFC and lead to overall lower activity in DA neurons and a dip in the DA response at the time of the reward (Figure 6B, top). Our suggested mechanism agrees with recent data that has shown that abnormal prediction errors are associated with negative symptoms in patients with schizophrenia (Moran et al., 2008; Gradin et al., 2011). Negative symptoms would arise, then, as noise in the prediction error computation due to noise in the PFC.


Improper activation of D1 and D2 receptors leads to excess noise in prefrontal cortex.

Avery MC, Krichmar JL - Front Comput Neurosci (2015)

Negative symptoms in schizophrenia. (A) Chorley and Seth (2011) developed a model demonstrating how dopamine reward prediction error signals may be learned through the balance of excitatory and inhibitory projections. Excitatory signals from sensory areas fire phasically and drive dopamine neurons during the time of the stimulus (S) and the reward (R). Inhibitory signals from the striatum, on the other hand, also drive dopamine neurons, resulting in a constant firing rate during the time of the reward when the stimulus is predictive of the reward. (B) Our model suggests that the D2 state should affect striatum projections to dopamine neurons (top). That is, a high D2 state would increase the strength of inhibition on DA neurons, resulting in an overall lower firing rate for DA neurons and a dip in response at the time of the reward, despite the stimulus being predictive of the reward. Because PFC neurons that project to the striatum are driven by the corollary discharge (CD) in our model, an abnormal corollary discharge, as may be occurring in schizophrenic patients, could ultimately lead to abnormal DA responses (bottom).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356073&req=5

Figure 6: Negative symptoms in schizophrenia. (A) Chorley and Seth (2011) developed a model demonstrating how dopamine reward prediction error signals may be learned through the balance of excitatory and inhibitory projections. Excitatory signals from sensory areas fire phasically and drive dopamine neurons during the time of the stimulus (S) and the reward (R). Inhibitory signals from the striatum, on the other hand, also drive dopamine neurons, resulting in a constant firing rate during the time of the reward when the stimulus is predictive of the reward. (B) Our model suggests that the D2 state should affect striatum projections to dopamine neurons (top). That is, a high D2 state would increase the strength of inhibition on DA neurons, resulting in an overall lower firing rate for DA neurons and a dip in response at the time of the reward, despite the stimulus being predictive of the reward. Because PFC neurons that project to the striatum are driven by the corollary discharge (CD) in our model, an abnormal corollary discharge, as may be occurring in schizophrenic patients, could ultimately lead to abnormal DA responses (bottom).
Mentions: The idea that a low firing rate leads to negative symptoms (Loh et al., 2007) conflicts with the high firing rate in the low D1/high D2 state of our model and fMRI data showing an elevated BOLD signal in the PFC of schizophrenic patients (Manoach et al., 1999). We propose, instead, that negative symptoms arise due to noise in the reward prediction error signal. To build upon this idea, we briefly introduce a model (Chorley and Seth, 2011) that is able to account for how reward prediction error signals take shape in midbrain dopamine neurons. In their model, Chorley and Seth suggest that inhibitory signals from the striatum, which are driven by the PFC, must match excitatory signals from subthalamic nucleus for DA neurons to fire phasically for a stimulus predictive of a reward (Figure 6A). Our model predicts that D2 levels would affect the neurons in the PFC that project to the striatum and, therefore, could alter the reward prediction error signal of dopamine neurons. A high D2 state, then, would increase activity in the PFC and lead to overall lower activity in DA neurons and a dip in the DA response at the time of the reward (Figure 6B, top). Our suggested mechanism agrees with recent data that has shown that abnormal prediction errors are associated with negative symptoms in patients with schizophrenia (Moran et al., 2008; Gradin et al., 2011). Negative symptoms would arise, then, as noise in the prediction error computation due to noise in the PFC.

Bottom Line: We developed a model that takes into account the known receptor distributions of D1 and D2 receptors, the changes these receptors have on neuron response properties, as well as identified circuitry involved in working memory.Our model suggests that D1 receptor under-stimulation in supragranular layers gates internal noise into the PFC leading to cognitive symptoms as has been proposed in attention disorders, while D2 over-stimulation gates noise into the PFC by over-activation of cortico-striatal projecting neurons in infragranular layers.We apply this model in the context of a memory-guided saccade paradigm and show deficits similar to those observed in schizophrenic patients.

View Article: PubMed Central - PubMed

Affiliation: Systems Neurobiology Laboratory, Salk Institute for Biological Studies San Diego, CA, USA.

ABSTRACT
The dopaminergic system has been shown to control the amount of noise in the prefrontal cortex (PFC) and likely plays an important role in working memory and the pathophysiology of schizophrenia. We developed a model that takes into account the known receptor distributions of D1 and D2 receptors, the changes these receptors have on neuron response properties, as well as identified circuitry involved in working memory. Our model suggests that D1 receptor under-stimulation in supragranular layers gates internal noise into the PFC leading to cognitive symptoms as has been proposed in attention disorders, while D2 over-stimulation gates noise into the PFC by over-activation of cortico-striatal projecting neurons in infragranular layers. We apply this model in the context of a memory-guided saccade paradigm and show deficits similar to those observed in schizophrenic patients. We also show set-shifting impairments similar to those observed in rodents with D1 and D2 receptor manipulations. We discuss how the introduction of noise through changes in D1 and D2 receptor activation may account for many of the symptoms of schizophrenia depending on where this dysfunction occurs in the PFC.

No MeSH data available.


Related in: MedlinePlus