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Review
. 2022 Jan 3:15:782947.
doi: 10.3389/fnins.2021.782947. eCollection 2021.

Morris Water Maze and Contextual Fear Conditioning Tasks to Evaluate Cognitive Functions Associated With Adult Hippocampal Neurogenesis

Karina Hernández-Mercado  1 , Angélica Zepeda  1
Affiliations
Review

Morris Water Maze and Contextual Fear Conditioning Tasks to Evaluate Cognitive Functions Associated With Adult Hippocampal Neurogenesis

Karina Hernández-Mercado et al. Front Neurosci. .

Abstract

New neurons are continuously generated and functionally integrated into the dentate gyrus (DG) network during the adult lifespan of most mammals. The hippocampus is a crucial structure for spatial learning and memory, and the addition of new neurons into the DG circuitry of rodents seems to be a key element for these processes to occur. The Morris water maze (MWM) and contextual fear conditioning (CFC) are among the most commonly used hippocampus-dependent behavioral tasks to study episodic-like learning and memory in rodents. While the functional contribution of adult hippocampal neurogenesis (AHN) through these paradigms has been widely addressed, results have generated controversial findings. In this review, we analyze and discuss possible factors in the experimental methods that could explain the inconsistent results among AHN studies; moreover, we provide specific suggestions for the design of more sensitive protocols to assess AHN-mediated learning and memory functions.

Keywords: behavioral protocols; brain damage; cognitive flexibility; functional recovery; hippocampal function; neurogenesis ablation; pattern separation; plasticity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Searching strategies used by rodents during spatial learning in the Morris water maze. (A) Spatial allocentric strategy (object to object) is characterized by the ability to navigate using distal cues located outside the maze and at some distance from the rodent. The bottom panel shows representative examples of three allocentric search strategies listed from most precise to least precise (direct swim→ focal swim → directed search), which have been related to AHN. (B) Non-spatial egocentric strategy (self to object) characterized by the ability to navigate using internal cues independent of external cues based on a sequence of bodily movements. The bottom panel presents representative examples of six spatially imprecise egocentric search strategies (chaining, scanning, random, thigmotaxis, and perseverance). The decrease in AHN has been related to more imprecise search strategies. (C,D) Example of the search strategies adopted by rodents with normal (C) and low levels of neurogenesis (D). The bottom bar charts illustrate the percentage of search strategies employed by rodents across training. Green bar: spatially precise search. Blue bar: spatially imprecise search. Gray bar: perseverance search. Rodents with low hippocampal neurogenesis require more training days before they begin to use spatially precise search strategies (green) than rodents with normal neurogenesis. When the platform changes to a new location, rodents with low neurogenesis spend more time searching over the old platform location (perseverance; gray bar) and adopt more imprecise search strategies (blue) than controls.
FIGURE 2
FIGURE 2
The roles of adult neurogenesis in different contextual fear-related behaviors. (A) Activation of adult born- neurons (yellow neurons) activates GABAergic inhibitory interneurons (red triangles) in the DG and CA3 (Restivo et al., 2015; Temprana et al., 2015), which may increase sparsity activity in the DG-CA3 circuit potentially promoting pattern separation. Left below, the function of pattern separation prevents interference among different neuron population codes that are active during two similar experiences: A (blue) vs. B (yellow). This process facilitates the ability of the animal to discriminate between the conditioned context (A, blue) and a similarly close safe context (sloping walls, B yellow, ➀). Through this mechanism, AHN may promote fear memory extinction by reducing the interference between an old aversive memory association (context with foot shock) and a new safe association (context with no foot shock, ➁). After fear memory extinction, the increase in AHN by environmental enrichment (EE) prevents spontaneous fear recovery ➂. (B) A decrease in adult born- neurons reduces sparsity activity in the DG-CA3 circuit which may impair pattern separation (Niibori et al., 2012; Denny et al., 2014). Bottom right, low neurogenesis impairs pattern separation, which decreases the ability of an animal to discriminate between closely similar contexts ➀. Impairment in pattern separation due to low neurogenesis may also impair fear memory extinction. Rodents with low neurogenesis are not able to reduce the conditioned fear response (freezing) as efficiently as mice with normal levels of neurogenesis (trial 2 vs. trial 3) during extinction training ➁. The reduction in AHN by irradiation (X-ray) promotes spontaneous fear recovery ➂.
FIGURE 3
FIGURE 3
Adult hippocampal neurogenesis and contextual fear learning and memory. (A) ➀ Immature new neurons between 4 and 6 weeks old (red, inside dotted square) are particularly important for hippocampal memory function. Immature new neurons available at the time of the training become a part of the memory trace: ➁ dotted circle, young neurons (red) connected (black lines) with mature neurons (yellow). However, if they are absent before training or optogenetically silenced during conditioning ➂, their contribution to the memory trace is restricted ➃. (B) As part of the memory trace, young neurons contribute to an adequate memory retrieval, which is reflected by freezing behavior. Pretraining ablation or silencing of new neurons during conditioning, impairs memory retrieval, which is reflected by diminished freezing behavior. If immature new neurons are silenced during retrieval ➄, memory impairment is observed (diminished freezing). This highlights the role of immature new neurons between 4 and 6 weeks old as a critical component of memory traces.
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