Mesocortical Pathway

The mesocortical pathway is one of the major dopamine pathways in the brain^[1]. The term "mesocortical" refers to the source and destination of this pathway – "meso" stands for "mesencephalic" (the technical term for the midbrain), and "cortical" refers to the cerebral cortex.

The mesocortical pathway originates in the ventral tegmental area (VTA) of the midbrain. From the VTA, dopaminergic neurons project and release dopamine into various regions of the cerebral cortex^[2].

The primary function of the mesocortical pathway is associated with cognition and emotion, with a particular focus on motivation and emotional response ^[4]. This pathway plays an essential role in the so-called "reward system" of the brain. It is involved in the regulation of executive functions, such as working memory, decision making, and attention ^[5].

The mesocortical pathway primarily interacts with the prefrontal cortex, a region critical for higher cognitive functions ^[6].

Neurons in the VTA produce dopamine. These neurons send projections via the mesocortical pathway to the prefrontal cortex, releasing dopamine there ^[7]. Dopamine release in the prefrontal cortex influences cognition by playing a role in working memory and attention - if you recall the definition of cognition, it is highly dependent on working memory to process information ^[8].

Working memory, which is responsible for temporarily holding and processing information, relies on the sustained and coordinated activity of groups of neurons in the prefrontal cortex (PFC) ^[9].

Signal-to-Noise Ratio: A key concept in neural processing is the "signal-to-noise ratio", which is essentially the differentiation between relevant (signal) and irrelevant (noise) information ^[10]. The prefrontal cortex is a highly associative area of the brain, receiving inputs from various sensory modalities and other cortical areas. These various inputs can be thought of as "signals" that need to be distinguished from "noise." Dopamine is thought to modulate the responsivity of PFC neurons in a way that amplifies the "signal" (i.e., relevant information) while suppressing the "noise" (i.e., irrelevant information). This can be crucial for maintaining the integrity of information in working memory ^[11].

The key is that dopamine does not have a uniform effect on all neurons or even on all parts of a single neuron. The impact of dopamine depends on various factors, including the type of dopamine receptor the neuron expresses, the location of these receptors on the neuron, and the current state of the neuron (i.e., whether it is firing action potentials or not) ^[12].

Dopamine works on the signal-to-noise ratio in the following ways:

1. Signal Amplification: Dopamine has been found to enhance the 'signal' by increasing the responsivity of certain neurons in the PFC to inputs that they are already responding to ^[13]. Dopamine can make these neurons more likely to fire in response to these inputs, essentially making the 'signal' stronger. This can help maintain the activity of neural circuits that are holding relevant information in working memory ^[14].

2. Noise Suppression: At the same time, dopamine can decrease the responsivity of these neurons to other, 'noisy' inputs that they are not already responding to. This makes it less likely that these neurons will be distracted by irrelevant information, effectively reducing the 'noise' ^[15].

The prefrontal cortex contains two main types of dopamine receptors: D1 and D2. These receptors have different effects on neurons^[16].

1. D1 receptors: These are generally excitatory, meaning that when they are activated by dopamine, they can increase the neuron's firing rate. They are often found on the 'body' (soma) and the main output branches (axon) of neurons. By activating D1 receptors, dopamine can increase the 'signal' by enhancing the firing of neurons in response to inputs they are already responding to^[17].

2. D2 receptors: These are generally inhibitory, meaning that when they are activated by dopamine, they can decrease the neuron's firing rate. They are often found on the input branches (dendrites) and the synaptic terminals of neurons. Activation of D2 receptors can help suppress the 'noise' by reducing the likelihood that the neuron will respond to 'noisy' inputs it receives^[18].

3. Modulation of other neurotransmitters: Dopamine can also influence the action of other neurotransmitters. For example, it can modulate the function of GABA (an inhibitory neurotransmitter) and glutamate (an excitatory neurotransmitter) neurons, thereby indirectly affecting the generation of action potentials^[18].

By selectively enhancing the firing of some neurons (those holding relevant information) and inhibiting the firing of others (those processing irrelevant 'noise'), dopamine can help to maintain the integrity of information in working memory, thus improving cognitive performance^[19].

The net effect of dopamine on a particular neuron in the PFC will depend on the balance of these different actions, as well as other factors like the current state of the neuron and the presence of other neurotransmitters^[20].

Neuronal Excitability and Connectivity: Dopamine also affects the excitability of neurons, i.e., how likely they are to fire. This modulatory effect can influence the connectivity between different neurons involved in a working memory task. Dopamine release can make certain neural pathways more likely to be used, thereby affecting the way information is processed and stored^[21].

Long-Term Potentiation (LTP): Dopamine is involved in the process of Long-Term Potentiation, which is a long-lasting enhancement in signal transmission between two neurons after synchronous stimulation. This mechanism is thought to be a key process in learning and memory. Dopamine can enhance LTP, thereby strengthening the connections between neurons and helping to consolidate the neural patterns that correspond to the information being held in working memory^[22].

The mesocortical pathway is one of the four major dopamine pathways in the brain, the others being the mesolimbic pathway, the nigrostriatal pathway, and the tuberoinfundibular pathway^[23].

The mesocortical and the mesolimbic pathways are often mentioned together because they both originate from the VTA. While the mesocortical pathway projects to the cerebral cortex, the mesolimbic pathway projects to the limbic system. These two pathways are central to the brain's reward circuit and are also implicated in several psychiatric conditions, including schizophrenia, mood disorders, and substance use disorder^[24].