Stress, depression, and neuroplasticity: a convergence of mechanisms. Christopher Pittenger and Ronald S Duman. Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA. Increasing evidence shows that neuroplasticity, a key mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. This review discusses how chronic stress, which can trigger or worsen depression, disrupts neuroplasticity, while antidepressants enhance it. The review covers neuroplasticity at different levels: structural (spine and dendrite morphology, adult neurogenesis), functional synaptic plasticity, and molecular and cellular mechanisms. These studies help elucidate mechanisms contributing to depression's pathophysiology. Understanding the convergence of mechanisms between stress, depression, and neuroplasticity may lead to new treatment targets. Antidepressants act on the brain's monoamine systems, and recent molecular events downstream of their actions have revealed new theories about depression's pathophysiology and antidepressant mechanisms. The transcription factor CREB, involved in synaptic plasticity and hippocampal antidepressant response, is a key example. Similar parallels exist in other molecular events, synaptic alterations, and morphological changes. While the precise relationship between depression's pathophysiology and neuroplasticity dysfunction is not fully understood, an intimate relationship likely exists. Chronic stress or dysregulated stress responses are increasingly linked to the molecular, cellular, and behavioral changes associated with depression-like states. Stress can lead to hippocampal atrophy similar to that seen in depression, and chronic stress paradigms in animals recapitulate many of depression's core behavioral characteristics and respond to antidepressants. Stress also affects neuroplasticity mechanisms, such as hippocampal synaptic plasticity, which is crucial for memory formation. Stress can impair long-term potentiation (LTP) in the hippocampus but enhance long-term depression (LTD) in rodents. Stress also damages hippocampal morphology and reduces neurogenesis, which may contribute to depression's development. The prefrontal cortex (PFC) is also affected by prolonged stress, leading to dendritic regression and impaired neuroplasticity. Stress reduces glial proliferation in the PFC, which may impact PFC function and morphology. The amygdala, in contrast, shows hypertrophy and hyperactivity in depression, with stress enhancing amygdala-dependent learning and synaptic plasticity. This contrast highlights the region-specific effects of stress on brain morphology and function. The ventral striatum, including the nucleus accumbens, is involved in reward mechanisms, and stress can alter its neuroplasticity, contributing to depression's symptoms. The molecular and cellular mechanisms of neuroplasticity include synaptic plasticity, which is regulated by calcium influx, cAMP, and kinases like CaMKII and PKA. CREB is a key transcription factor involved in synaptic plasticity and is enhanced by antidepressants.Stress, depression, and neuroplasticity: a convergence of mechanisms. Christopher Pittenger and Ronald S Duman. Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA. Increasing evidence shows that neuroplasticity, a key mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. This review discusses how chronic stress, which can trigger or worsen depression, disrupts neuroplasticity, while antidepressants enhance it. The review covers neuroplasticity at different levels: structural (spine and dendrite morphology, adult neurogenesis), functional synaptic plasticity, and molecular and cellular mechanisms. These studies help elucidate mechanisms contributing to depression's pathophysiology. Understanding the convergence of mechanisms between stress, depression, and neuroplasticity may lead to new treatment targets. Antidepressants act on the brain's monoamine systems, and recent molecular events downstream of their actions have revealed new theories about depression's pathophysiology and antidepressant mechanisms. The transcription factor CREB, involved in synaptic plasticity and hippocampal antidepressant response, is a key example. Similar parallels exist in other molecular events, synaptic alterations, and morphological changes. While the precise relationship between depression's pathophysiology and neuroplasticity dysfunction is not fully understood, an intimate relationship likely exists. Chronic stress or dysregulated stress responses are increasingly linked to the molecular, cellular, and behavioral changes associated with depression-like states. Stress can lead to hippocampal atrophy similar to that seen in depression, and chronic stress paradigms in animals recapitulate many of depression's core behavioral characteristics and respond to antidepressants. Stress also affects neuroplasticity mechanisms, such as hippocampal synaptic plasticity, which is crucial for memory formation. Stress can impair long-term potentiation (LTP) in the hippocampus but enhance long-term depression (LTD) in rodents. Stress also damages hippocampal morphology and reduces neurogenesis, which may contribute to depression's development. The prefrontal cortex (PFC) is also affected by prolonged stress, leading to dendritic regression and impaired neuroplasticity. Stress reduces glial proliferation in the PFC, which may impact PFC function and morphology. The amygdala, in contrast, shows hypertrophy and hyperactivity in depression, with stress enhancing amygdala-dependent learning and synaptic plasticity. This contrast highlights the region-specific effects of stress on brain morphology and function. The ventral striatum, including the nucleus accumbens, is involved in reward mechanisms, and stress can alter its neuroplasticity, contributing to depression's symptoms. The molecular and cellular mechanisms of neuroplasticity include synaptic plasticity, which is regulated by calcium influx, cAMP, and kinases like CaMKII and PKA. CREB is a key transcription factor involved in synaptic plasticity and is enhanced by antidepressants.