**4.4 The prefrontal cortex**

The hippocampus and the prefrontal cortex are closely related to advanced cognitive functions of the brain such as learning and memory [50]. Previous studies showed that neural projections from the hippocampus to the prefrontal cortex had the characteristics of a single synapse, were unidirectional, and displayed ipsilateral projections [51]. In brief, the hippocampus-prefrontal lobe projection mainly originates from the subiculum of the ventral hippocampus and the CA1 and ends in the medial, orbitofrontal, and lateral parts of the prefrontal lobe (**Figure 4**). The projection from the prefrontal lobe to the hippocampus is indirectly from the prefrontal lobe to the cingulate gyrus, parahippocampal gyrus, entorhinal cortex, then to the hippocampus [52], which transmits information from prefrontal lobes to important nuclei of the hippocampus [53, 54]. There are also reports that some nerve fibers in the prefrontal lobe project directly to the hippocampus, but the number was low [55, 56].

**Figure 4.** *The pathway from the hippocampus to the prefrontal cortex.*

Humans are faced with different environments every day and need to make the right choices through learning and memory in order to find their goals. A recent study [5] found that when an animal runs a specific route and then stops to rest or sleep, place cells [3] are repeatedly released in the same (forward) or opposite (reverse) order as when it ran, and at a faster rate than animals' running. This phenomenon is called memory replay, and this replay has a very important role in the prefrontal cortex circuit which helps the animal remember the path it has taken in the past and makes the right choice among multiple alternative paths.

To understand hippocampus-prefrontal cooperative activities during memory replay and whether memory replay affects animal learning and decision-making, researchers trained rats to learn to find their way in a W-maze [57]. In this task, the rat needs to learn two different rules to get the reward, a simple task and a complex task—in the simple task, the animal only needs to remember the beginning and end positions, then they can successfully find and get the reward; in the complex task, the animal needs to remember the path it has just run and then select the path it has not passed yet among the two available paths to get a reward, this process requires working memory. In this task, most of the memory replay occurred when the animals stayed at the reward site, had just completed a path, or were about to choose the next path [58–61]. The study found that the hippocampus was involved in the processes of both reverse and forward replay. Further studies analyzed whether the content of the hippocampus forward and reverse memory replays changed with learning. They found that the content of forward and reverse replay is different in the different learning stages. In the early stage of learning, reverse replay preferred to the paths that the animal had actually passed before, and thus researchers could accurately predict the animal's past choices from the content of the hippocampal reverse replay. In contrast, forward replay referred to the pathway that the animal will choose next, but this correspondence does not become apparent until later in learning. The dynamic processes of hippocampal reverse and forward replays in the learning process showed that reverse memory replay was very important for animals to remember the past path for learning, and the forward replay was very important for action planning after zoological learning [62, 63]. Besides the W-maze, we can also use the Barnes maze [64] to get the same conclusion. In summary, this study first distinguished the different functions of hippocampal reverse and forward memory replays in spatial learning memory tasks. Reverse memory replay helps to weigh and remember the path to the goal in the past, while forward memory replay is important for planning actions in the future. Moreover, this study for the first time quantitatively described the replay of cooperative memory between the prefrontal cortex and the hippocampus and confirmed its association with animal behavioral choices, to suggest a possible mechanism for the prefrontal cortex to participate in spatial learning.

### **4.5 vDBChATs-dNGIs**

Acetylcholine modifies neuronal excitability, alters presynaptic neurotransmitter release, and coordinates the firing of groups of neurons [65–67]. Recently, researchers used optogenetics, single synaptic tracing, and electrophysiological recording techniques to show that cholinergic neurons in the vertical diagonal band of Broca (vDBChATs) and newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice formed a single synaptic connection (vDB-ChATs-dNGIs synaptic connection) (**Figure 5**); this synaptic transmission was essential for the survival of dNGIs, andthe vDBChATs directly innervate dNGIs. This circuit is mediated by muscarinic cholinergic receptor 1 (M1) on neonatal neurons [68]. In this study, researchers injected a kind of virus that includes mCherry

*Neural Circuits and Some New Factors Involved in Hippocampal Memory DOI: http://dx.doi.org/10.5772/intechopen.101309*

into the vDB region of some mice. Three days later, in the dDG, mCherry was exclusively expressed in a group of granular cells that were predominately located in the inner one-third of the granule cell layer. Most of these mCherry+ cells expressed doublecortin (DCX, mCherry+DCX+). DCX has been widely established as a marker of immature neurons [69], so mCherry+DCX+ cells are one kind of newly generated NGIs in the dNGIs mentioned above. The study found that using optogenetic technology to enhance vDBChATs-dNGIs synaptic transmission improved spatial learning memory. Furthermore, in the AD transgenic mouse model, the use of optogenetic technology to enhance the synaptic transmission of the neural circuit saved the spatial memory loss of the model mice [70].
