Synapse Regression in Depression: The Role of 5-HT Receptors in Modulating NMDA Receptor Function and Synaptic Plasticity

Depression is accompanied by an increase in activity in the amygdala and a decrease in the rostral anterior cingulate cortex (rACC), with the former attributed to a failure of the latter to exert its normal inhibitory influence. This failure is likely due to regression of synaptic connections between the rACC and the amygdala, a process reversed in part by selective serotonin reuptake inhibitors (SSRIs). The present work presents a hypothesis as to how SSRIs might bring about this process and hence normalization of activity, at least in patients that are responsive to SSRIs. Serotonin receptors of the excitatory 5-HT2AR class increase N-methyl-D-aspartate receptor (NMDAR) efficacy, while those of the inhibitory 5-HT1AR class decrease NMDAR efficacy. A decrease of 5-HT transporter (5-HTT) efficacy, either during human development through functional polymorphisms, or in animals through 5-HTT transgenic knockouts, is accompanied by a decrease in 5-HT1AR and hence an increase in excitability and NMDAR efficacy which drives an increase in synaptic spines in the amygdala. As the limbic region of the brain normally possesses high levels of 5-HT1AR the effect of loss of these is to increase excitation in this region, as is observed. Changes in the level of extracellular 5-HT in adult animals also modulates the density of synaptic spines, with these increasing with an increase in 5-HT, possibly as a consequence of increases in 5-HT2AR activity over that of 5-HT1AR. Increasing extracellular levels of 5-HT with SSRIs would then lead to an increase in excitability and in synaptic spines for afferents in the dorsal rostral anterior cingulate cortex but not in the ventral regions such as the amygdala that have few 5-HT2AR. This allows dorsal regions to once more exert their inhibitory influence over ventral regions. In this way, SSRIs may exert their effect in normalizing dorsal hypometabolism and ventral hypermetabolism in those suffering from depression.

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The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EEG, fMRI, and volumetric techniques

NeuroImage ◽

10.1016/j.neuroimage.2009.01.058 ◽

2009 ◽

Vol 46 (1) ◽

pp. 327-337 ◽

Cited By ~ 236

Author(s):

Jan Wacker ◽

Daniel G. Dillon ◽

Diego A. Pizzagalli

Keyword(s):

Nucleus Accumbens ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Rostral Anterior Cingulate Cortex

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The Neural Basis of Predictive Pursuit

10.1101/694604 ◽

2019 ◽

Cited By ~ 2

Author(s):

Seng Bum Michael Yoo ◽

Jiaxin Cindy Tu ◽

Steven T. Piantadosi ◽

Benjamin Yost Hayden

Keyword(s):

Anterior Cingulate Cortex ◽

Real Time ◽

Critical Role ◽

Cingulate Cortex ◽

Explicit Representation ◽

Anterior Cingulate ◽

Neural Basis ◽

Dorsal Anterior Cingulate Cortex ◽

The Brain

ABSTRACTIt remains unclear how and to what extent non-human animals make demanding on-the-fly predictions during pursuit. We studied this problem in a novel laboratory pursuit task that incentivizes prediction of future prey positions. We trained three macaques to perform joystick-controlled pursuit of prey that followed intelligent escape algorithms. Subjects reliably aimed towards the prey’s likely future positions, indicating that they generate internal predictions and use those predictions to guide behavior. We then developed a generative model that explains real-time pursuit trajectories and showed that our subjects use prey position, velocity, and acceleration to make predictions. We identified neurons in the dorsal anterior cingulate cortex (dACC) whose responses track these three variables. These neurons multiplexed prediction-related variables with a distinct and explicit representation of the prey’s future position. Our results provide a clear demonstration that the brain can explicitly represent future predictions and highlight the critical role of anterior cingulate cortex for future-oriented cognition.One-sentence summaryIn a dynamic pursuit environment, monkeys actively predict future prey positions and dACC neurons encode these future positions.

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