ARCHIVAL REPORT Learning as a Model for Neural Plasticity in Major Depression Christoph Nissen, Johannes Holz, Jens Blechert, Bernd Feige, Dieter Riemann, Ulrich Voderholzer, and Claus Normann Background: The neuroplasticity hypothesis of depression proposes that a dysfunction of neural plasticity—the basic ability of living organisms to adapt their neural function and structure to external and internal cues—might represent a final common pathway underlying the biological and clinical characteristics of the disorder. This study examined learning and memory as correlates of long-term synaptic plasticity in humans to further test the neuroplasticity hypothesis of depression. Methods: Learning in three tasks, for which memory consolidation has been shown to depend on local synaptic refinement in areas of interest (hippocampus-dependent declarative word-pair learning, amygdala-dependent fear conditioning, and primary-cortex-dependent visual texture discrimination), was assessed in 23 inpatients who met International Classification of Disease, 10th Revision, criteria for severe unipolar depression and 35 nondepressed comparison subjects. Results: Depressed subjects showed a significant deficit in declarative memory consolidation and enhanced fear acquisition as indicated by skin conductance responses to conditioned stimuli, in comparison with nondepressed subjects. Depressed subjects demonstrated impaired visual discrimination at baseline, not allowing for valid group comparisons of gradual improvement, the plasticity-dependent phase of the task. Conclusions: The results of the study are consistent with the neuroplasticity hypothesis of depression, showing decreased synaptic plasticity in a dorsal executive network that comprises the hippocampus and elevated synaptic plasticity in a ventral emotional network that includes the amygdala in depression. Evaluation of further techniques aimed at modulating synaptic plasticity might prove useful for developing novel treatments for major depressive disorder. Key Words: Depression, fear conditioning, human, memory, syn- aptic plasticity, texture discrimination M ajor depressive disorder (MDD) is the leading cause of years of life lived with disability across all ages worldwide. Still, less than 50% of all individuals with MDD show full remission with optimized first-line treatment, indicating the need for additional research (1). The Neuroplasticity Hypothesis of Depression A novel but as yet unconfirmed concept for the etiology of MDD proposes that a dysfunction of neural plasticity—the basic ability of living organisms to adapt their neural function and structure to external and internal cues in a changing environment—might rep- resent a final common pathway underlying the biological and clin- ical characteristics of the disorder (2). Some data suggest that changes in neurogenesis might be linked to the pathophysiology of MDD. A decrease in neurogenesis has been shown in animal models of depression (3,4) and treatment with antidepressants increased the number of surviving newborn neurons in adult rodents (5–7). Research on neurogenesis might ultimately lead to new therapies for neural degeneration or lesions. However, it is unlikely that neurogenic processes, which have been demonstrated to be limited to the dentate gyrus of the hippocam- pus and the olfactory bulb in adult rodents (8), represent a sufficient mechanism to explain the broad spectrum of biological and clinical alterations in MDD (9). More recently, the idea has been put forward that shifts in syn- aptic plasticity and related network activity might be critical for the development of MDD (2,10 –13). In contrast to neurogenesis, long- term potentiation (LTP) and long-term depression (LTD)—two ba- sic mechanisms for experience-dependent modification of synaptic strength— have been described in virtually every brain region across species, including humans (14 –17). Electrophysiological studies revealed that chronic mild stress facilitates hippocampal LTD in an animal model of depression (3). Other models of chronic stress have also demonstrated an impairment in LTP (18 –20). Recently, our group reported that the modulation of early com- ponents of the visual evoked potential shares properties with Heb- bian forms of synaptic plasticity and is altered in depressed subjects relative to nondepressed ones (13). This has been interpreted as the first evidence for reduced LTP-dependent plasticity in the cortex of patients with MDD (21). Despite the promise of this line of research, fundamental questions persist regarding the subtypes of plasticity, the distribution of plastic changes across brain networks, and the relationship of these changes to the clinical symptoms of the disor- der. Neurocircuitry Models of Depression Current models emphasize the relevance of two neural sys- tems in emotional behavior: a ventral emotional system, com- prising the amygdala, insula, ventral striatum, and ventral parts of the anterior cingulate cortex and prefrontal cortex and a dorsal executive system, comprising the hippocampus, the dor- sal anterior cingulate cortex, and the dorsolateral prefrontal cortex (22). Studies have suggested that the ventral system has increased activity, whereas the dorsal system has decreased From the Department of Psychiatry (CN, JH, BF, DR, UV, CN), University Medical Center Freiburg, Freiburg, Germany; Department of Psychology (JB), University of Freiburg, Freiburg, Germany; Department of Psychol- ogy (JB), Stanford University, Palo Alto, California; and Schön Klinik Rose- neck (UV), Prien am Chiemsee, Germany. Address corespondence to Christoph Nissen, M.D., Department of Psychia- try and Psychotherapy, University Medical Center Freiburg, Haupt- strasse 5, 79104 Freiburg, Germany; E-mail: christoph.nissen@uniklinik- freiburg.de. Received Feb 2, 2010; revised May 17, 2010; accepted May 19, 2010. BIOL PSYCHIATRY 2010;xx:xxx 0006-3223/$36.00 doi:10.1016/j.biopsych.2010.05.026 © 2010 Society of Biological Psychiatry ARTICLE IN PRESS