Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

Abstract

During the last decade, the questions on the functionality of adult neurogenesis have changed their emphasis from if to how the adult-born neurons participate in a variety of memory processes. The emerging answers are complex because we are overwhelmed by a variety of behavioral tasks that apparently require new neurons to be performed optimally. With few exceptions, the hippocampal memory system seems to use the newly generated neurons for multiple roles. Adult neurogenesis has given the dentate gyrus new capabilities not previously thought possible within the scope of traditional synaptic plasticity. Looking at these new developments from the perspective of past discoveries, the science of adult neurogenesis has emerged from its initial phase of being, first, a surprising oddity and, later, exciting possibility, to the present state of being an integral part of mainstream neuroscience. The answers to many remaining questions regarding adult neurogenesis will come along only with our growing understanding of the functionality of the brain as a whole. This, in turn, will require integration of multiple levels of organization from molecules and cells to circuits and systems, ultimately resulting in comprehension of behavioral outcomes.

Figure 1.

The trisynaptic circuit. (A) The mammalian hippocampus is organized into transverse sections. Each section includes most of the anatomical components comprising the so-called trisynaptic circuit. (B) The first relay in this circuit includes synapses between cortical afferents projecting from the entorhinal cortex (EC) to the dentate gyrus (DG) and the granule neurons arranged in a semicircle. The second relay is located in the CA3 field and consists mainly of the mossy fiber synapses on CA3 pyramidal neurons. The mossy fibers are the axon terminals of the granule neurons. The third relay is in the CA1 field and consists of the axon terminals of CA3 neurons contacting CA1 neurons. This trisynaptic circuit makes up a scaffold for more detailed interconnections within each of the main regions: DG, CA3, and CA1.

Figure 2.

Spaghetti strainer experiment illustrates pattern separation (PS). Each of the small pores at the bottom of the strainer represents a granule neuron transmitting signals from combined afferent inputs. Because of dispersal of the inputs by the random action of each pore, the output at the bottom consists of an array of unique patterns that are quite different from each other although the input streams are similar.

Figure 3.

Event separation on the basis of a critical period. Event separation can be considered as a form of behavioral PS because two similar events may have to be tagged in some way to be unambiguously recalled later on. This tagging mechanism may or may not be the same as during the separation of simultaneous events. One possible mechanism, shown here, is based on the known transition of new neurons through the time-dependent developmental window (critical period between 3–6 wk of age). One cohort with a window corresponding to event 1 will be closed during event 2. However, a second cohort will be open during event 2 and can provide a substrate for encoding.

Figure 4.

Role of adult-born neurons in memory interference. (A) Time line of an experiment showing memory interference after ablation of adult neurogenesis by irradiation. Each animal was tested twice: first, on a new set of paired olfactory discrimination stimuli (list 1) and, next, on another set (list 2). List 2 was presented in the same or different context as list 1. (B) The results show that memory of list 1 was not changed by irradiation, but the memory of list 2 was made worse regardless of context. Thus, context/memory association was neurogenesis dependent. N.S., Not significant. (Figures based on data in Luu et al. 2012.)

Figure 5.

Summary of possible behavioral outcomes resulting from imbalance between pattern separation (PS) and pattern completion. (Top) In control conditions, the dentate gyrus (DG) serves as a pattern separator functioning under a normal inhibitory tone supplied by inhibitory interneurons. Disinhibited granule neurons (open circles) are proportionally fewer than the inhibited granule neurons (filled circles). The loop around CA3 field illustrates normal activity of recurrent collaterals in this region. Their function is to connect the adjacent CA3 neurons and accomplish pattern completion. (Middle) Reduced pattern separation resulting from reduced inhibitory tone, such as during conditions of reduced neurogenesis. An extreme case of all granule neurons being disinhibited is shown. This could result in a loss of PS and exaggerated pattern completion in CA3 as a result of excessive input from mossy fiber afferents. The reduced PS and increased pattern completion could contribute to abnormal hippocampal function in conditions such as anxiety, depression, and mild cognitive impairment (MCI). (Bottom) Increased PS, resulting from increased inhibitory tone because of abnormally enhanced adult neurogenesis. In this case, most granule neurons are inhibited and unable to transmit signals to CA3. PS is extreme and the resulting pattern completion in CA3 is also low. Possible behavioral conditions could include autism, obsessive attention to detail, and obsessive–compulsive disorder (OCPD).