Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood

Abstract

Adult hippocampal neurogenesis has been implicated in cognitive processes, such as pattern separation, and in the behavioural effects of stress and antidepressants. Young adult-born neurons have been shown to inhibit the overall activity of the dentate gyrus by recruiting local interneurons, which may result in sparse contextual representations and improved pattern separation. We propose that neurogenesis-mediated inhibition also reduces memory interference and enables reversal learning both in neutral situations and in emotionally charged ones. Such improved cognitive flexibility may in turn help to decrease anxiety-like and depressive-like behaviour.

Figure 1 |. The ventral hippocampus and the neural circuitry of mood and anxiety.

The figure shows a simplified representation of the ventral hippocampus and its place within the circuits that are implicated in mood and anxiety. The basolateral amygdala (BLA) provides cholinergic input to the medial septum and glutamatergic input to the entorhinal cortex, which both send inputs to and can enhance ventral hippocampus activity to increase fear and anxiety-like responses. Direct projections from CA1 in the ventral hippocampus provide feedforward inhibition by activating BLA interneurons. The ventral hippocampus also sends glutamatergic project ions to GABAergic medium spiny neurons in the nucleus accumbens (NAc) to regulate NAc control over dopamine release from the ventral tegmental area (not shown). Ventral hippocampus-to-NAc projections promote reward-seeking behaviour in the absence of stress but induce anxiety-like and depressive-like behaviour during stress. Direct projections from the ventral hippocampus to the medial prefrontal cortex (mPFC) promote anxiety and stress susceptibility and are also involved in antidepressant effects. Glutamatergic projections from the ventral hippocampus activate GABAergic interneurons in the bed nucleus of the stria terminalis (BNST). These interneurons inhibit neurosecretory neurons in the paraventricular nucleus (PVN) of the hypothalamus. PVN neurons release corticotropin-releasing hormone, which stimulatesthe production of adreno-corticotropic hormone (ACTH) in the pituitary gland. ACTH stimulatesthe production and release of glucocorticoids from the adrenal cortex into the bloodstream. Glucocorticoids exert feedback inhibition on the hypothalamus–pituitary–adrenal axis by activating glucocorticoid and mineralocorticoid receptors in the pituitary gland, hypothalamus and hippocampus. Consistently high levels of glucocorticoids during conditions of chronic stress can reduce hippocampal neurogenesis and cause neuronal atrophy^,.

Figure 2 |. Neurogenesis facilitates cognitive flexibility by allowing the formation of new distinct memory traces.

Contextual memories, such as where a safety platform is hidden in a Morris water maze, are encoded by neuronal ensembles in the dentate gyrus. These cellular representations of a memory are known as memory traces or engrams. a | With high neurogenesis, engrams may be cleared faster and transmitted to downstream processing structures. Efficient memory clearance reduces proactive interference between the memory of the previous location and the ability to accurately encode a novel location. This may facilitate reversal learning and cognitive flexibility to promote the finding of a new safety platform once the location has been changed^,,. b | With low neurogenesis, engrams of previous contexts may not be cleared sufficiently. As a result, novel contextual contingencies may not be encoded appropriately by distinct neuronal ensembles. This may increase proactive interference, reduce cognitive flexibility and impair the ability to find the new location of a hidden safety platform.

Figure 3 |. Neurogenesis promotes efficient stress recovery.

High or low levels of adult hippocampal neurogenesis do not influence baseline hypothalamus–pituitary–adrenal (HPA) axis activity, fear responses, innate anxiety, despair or anhedonia in rodents^,,. During stressful experiences, neuroendocrine responses and anxiety-like and depressive-like behaviour are less increased in mice with high levels of neurogenesis (part a) than in mice with low levels of neurogenesis^, (part b). Once the stressor has ended, neurogenesis facilitates reversal learning and cognitive flexibility to promote positive adaptation to novel, non-threatening environments. Therefore, increasing neurogenesis may facilitate fast recovery from HPA axis hyperactivity and anxiety-like and depressive-like behaviours and may prevent the development of chronic stress-induced psychopathology (part a).

Figure 4 |. Potential methods of harnessing the function of adult-born neurons to treat dentate gyrus-dependent mood and anxiety disorders.

To harness adult hippocampal neurogenesis as a treatment for depression and anxiety, patients with reduced neurogenesis or patients with neurogenesis-dependent impairments in dentate gyrus (DG) function will first need to be identified (left panel). Possible diagnostic measures could include imaging technigues of cerebral blood volume (CBV) in the DG, which has been shown to correlate with levels of neurogenesis; positron emission tomography (PET) using markers for neurogenesis that are currently being developed in mice; and magnetic resonance spectroscopy (MRS) of the 1.28 ppm peak, which has been suggested to indicate levels of proliferating neural progenitor cells. In vitro models, such as human induced pluripotent stem cells (hiPSCs), could be used to grow granule-like neurons from patient-specific skin or hair cells. This may allow the testing of the effect of stress hormones or antidepressants on neurogenesis in culture. Neurocognitive testing could also be used to identify patients with DG-dependent cognitive impairments. These tests could involve pattern separation tasks^– or virtual-reality memory tasks with a spatial navigation component, as patients with depression have an impaired performance in these tasks. Once patients with neurogenesis deficits or DG impairments have been identified, treatments could be used that have been shown to reliably increase neurogenesis in rodent models, such as exercise, learning-based approaches and selective serotonin reuptake inhibitors (SSRIs). Cognitive strategies might include brain-training games, which have been shown to improve reversal learning and cognitive flexibility and to engage mood-relevant neural circuitry. The development of future pharmacologicaltargets should be aimed at compoundsthat can increase neurogenesis orthat can inhibit mature granule cells and DG activity in patients. Enhancing neurogenesis and improving DG function in patients with confirmed impairments may increase cognitive flexibility and reduce hypothalamus–pituitary–adrenal (ElPA) axis hyperactivity, anxiety, negative attention bias and negative affect. Treating these impairments may facilitate efficient stress recovery and prevent or counteract the development of chronic psychopathology.