Uncovering antidepressive mechanisms of glutamatergic antagonism through neurocircuit, metabolic and morphological brain changes in a genetical rat model of depression
Human Cognitive and Systems Neuroscience
Final Report Abstract
In our first project we have found that stress-resilient and stress-susceptible genetical rat strains exhibit differential response to stress, reorganizing their brain topology in fundamentally different ways. As compared to the resilient strain, the risk strain enhanced an internodal role of the prefrontal cortical regions, such as the anterior cingulate and prelimbic cortices, and reduced their role within the regional neighborhood, expressed as decreased clustering and efficiency. The increased internodal role of these prefrontal regions could be due to the enhancement of their long-range connections, given their connectivity with the amygdala and other default-mode-like network hubs, which could create a bias to attend to negative information and result in stress susceptibility and depression. The knowledge on the functional pathways underlying stress vulnerability provides neuroanatomical targets whose activity could be modulated in order to induce stress resilience and prevent development of depression. In the second study we have demonstrated that ketamine and NR2B receptor antagonists had acute common effects on the circuitry mediating reward and cognitive aspects of emotional processing, localized to the same brain regions as those reported in depression, but in the opposite direction. Since, unlike ketamine, NR2B-selective drugs have improved therapeutic efficiency and side effect profile due to sparing of non-NR2B receptors, the knowledge on common circuits, where their effects intersect, provides a translational imaging phenotype for testing putative antidepressants. In the third study using genetical rat model of depression we identified two distinct phases of ketamine’s action. The rapid response at 30 min entailed robust and strain-independent topological modifications in cognitive, sensory, emotion and reward-related circuitry, including regions which exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine’s dissociative and antidepressant properties. At 48h ketamine had mainly strain-specific action normalizing habenula, mediodorsal thalamus and hippocampal connectivity measures in depressed rats. These nodes mediate cognitive flexibility, a deficit of which leads to an impaired ability to switch behaviors adaptively despite negative outcomes, as well as inability to process contextual information, to distinguish contextual cues in safe versus threatening situations and to modulate fear and emotional response in non-threatening environment. Action within this circuitry presumably reflects ketamine’s pro-cognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. We suggest that habenula, mediodorsal thalamus and dorsal hippocampus, directly involved in cognitive flexibility and whose topological normalization represented a key imaging correlate of ketamine’s longitudinal effect, should be investigated in the context of refined modulation of their circuitry to identify substrates of stress resilience/susceptibility in order to prevent the development of maladaptive behavior in response to stress.
Publications
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An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7. European Neuropsychopharmacology 2016 26(7):1150-60
Gass N, Weber-Fahr W, Sartorius A, Becker R, Didriksen M, Stensbøl TB, Bastlund JF, Meyer-Lindenberg A, Schwarz AJ
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Brain network reorganization differs in response to stress in rats genetically predisposed to depression and stress-resilient rats. Translational Psychiatry 2016 6(12):e970
Gass N, Becker R, Schwarz AJ, Weber-Fahr W, Clemm von Hohenberg C, Vollmayr B, Sartorius A
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Species-conserved reconfigurations of brain network topology induced by ketamine. Translational Psychiatry 2016 6:e786
Becker R, Braun U, Schwarz AJ, Gass N, Schweiger JI, Weber-Fahr W, Schenker E, Spedding M, Clemm von Hohenberg C, Risterucci C, Zang Z, Grimm O, Tost H, Sartorius A, Meyer-Lindenberg A
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Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior. Psychopharmacology (Berl). 2018 235(4):1055-1068
Gass N, Becker R, Sack M, Schwarz AJ, Reinwald J, Cosa-Linan A, Zheng L, von Hohenberg CC, Inta D, Meyer-Lindenberg A, Weber-Fahr W, Gass P, Sartorius A
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The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity. European Neuropsychopharmacology 2018 28(9):1035-1046
Tollens F, Gass N, Becker R, Schwarz AJ, Risterucci C, Künnecke B, Lebhardt P, Reinwald J, Sack M, Weber-Fahr W, Meyer-Lindenberg A, Sartorius A
