9.3: Neural Structures Involved in Memory and Learning

In the previous section, we saw the effects that removing the hippocampus and other parts of the medial temporal lobe had on HM’s memory. In this section, we look a little more deeply at the function and anatomy of structures that are important for memory.

The Hippocampus (HPC)

The hippocampus (HPC), meaning “seahorse” in Greek, was named based on its morphology. The HPC is located along the ventral and medial surface of the brain. The HPC is one of the critical structures of the limbic system, a series of subcortical brain structures that are involved in several different complex behaviors, such as emotions and memory. The limbic system is an evolutionarily ancient brain network.

The synaptic connectivity of the hippocampus is very well characterized. Hippocampal synaptic connectivity was first described by Ramon y Cajal, and is made up of three main synaptic connections; sometimes called the trisynaptic circuit. First, the axonal outputs of layers 2 and 3 from the entorhinal cortex make up the inputs into the HPC. This white matter signaling tract is called the perforant pathway, and they synapse onto the granule cells of the dentate gyrus. These neurons send axons, called mossy fibers, to the pyramidal cells of the Cornu ammonis (CA) 3 region of the HPC. The axonal projections from here, called Schaffer collaterals, project into CA1, which are the neurons that make up the output of the hippocampus. These outputs project out to layer 5 and 6 of entorhinal cortex. While the three main neuronal projections are glutamatergic, the trisynaptic circuit is modulated by GABA, acetylcholine, norepinephrine, and serotonin.

The HPC is involved in spatial memories, memories involved in navigation of our surroundings and the creation of a mental map of our world. Spatial memories are developed when we enter a new building for the first time, and we search for a new classroom. We also use our spatial memory whenever we are walking around campus, making our way from one building to another, thinking about the streets you’d need to cross or the buildings you can cut through. While the volume of the hippocampus is not a reliable indicator of the strength of a healthy person’s spatial memory, injury to the hippocampus causes deficits in spatial memory.

One spatial memory test that is regularly used in rodents is called the Morris water maze. In this test, a shallow pool is filled with an opaque liquid, making it difficult to see through. Hidden somewhere in this pool is a clear plexiglass platform, and there are different environmental cues (such as different colored shapes) surrounding the pool that can be seen from the surface of the water. The water is deep enough that when a rodent is put into the water maze, they have to swim to stay afloat. The rodents swim around aimlessly until they find the platform, the time it takes for this to happen is recorded, and the trial ends. Over time, the animals learn that the platform is located near certain navigational cues, and on future trials, the animals spend more time near those cues, and the latency to find the platform decreases. When the HPC is surgically removed from rodents or inactivated, they perform poorly in the Morris water maze.

Another non-human behavioral test used to assess the capacity for learning navigational cues is the radial arm maze. In this test, a rodent is placed on a circular platform. Extending from this platform are eight or more “arms”, at the end of each is a small dish. In one of the dishes is a morsel of food (“rewarded arm”), while the other dishes contain nothing (“non-rewarded arms”). The maze is designed so that the food cannot be seen from the end of each arm, so the animal must return to the starting platform before exploring another arm. The number of entries into a non-rewarded arms is counted as an error. Over time, the animals make fewer errors as they learn which arm is rewarded and which ones are not. Alzheimer’s disease model organisms perform poorly on this task.

Based on the deficits seen in Patient HM and other experimental manipulations of the HPC, we conclude that the HPC is strongly implicated in the process of declarative memories and spatial navigation. Since some of HM’s memory functions were still intact, such as procedural memories and working memory, it is believed that these functions are independent of HPC function.

The Amygdala

The amygdala is another limbic system structure found in the medial temporal lobe adjacent to the HPC that is important for experiencing emotion and emotional memories. The word amygdala comes from the Greek word meaning “almond,” which roughly describes its shape. While the amygdala is often spoken of as a single structure, it is more accurately divided into several subnuclei, each with different cell populations and functions. One broad division distinguishes the basolateral amygdala (BLA) versus the central nucleus of amygdala (CeA): The BLA contributes to both fear memories and reward processing, while the CeA contributes more to the physiological response in emotions as well the perception of emotion.

The amygdala is strongly involved with the formation and storage of emotional memories, memories or associations that have a strong emotional connection. Both positive and negative emotional states activate the amygdala. For example, a whiff of grandmother’s cooking may cause you to reminisce back to a fun childhood summer. Alternatively, the smell of vomit may elicit the unpleasant emotions and nausea associated with a nasty food poisoning incident.

One non-human test of emotional memory is the foot-shock paradigm, a form of classical conditioning called fear conditioning. This test involves putting a rodent into a chamber with floors made of metal rods, which are connected to an electric current generator. The metal rods can deliver a non- lethal but painful electric shock to the rodent’s foot. In this learning paradigm, a combination of sound and light cues is presented to the animal. Shortly after, the painful foot shock is delivered. If the animal learns that the cues are associated with the negative painful memory, they exhibit freezing after exposure to the cues. Amygdala lesions prevent the animal from freezing, while hippocampal lesions have no effect on this emotional learning. Changing cellular signaling in the amygdala alters the learning of fear conditioning. The foot-shock paradigm is often used as a non-human model of post-traumatic stress disorder.

Inferotemporal cortex (IT)

Structures of the inferotemporalcortex (IT) are part of the ventral stream of visual perception (chapter 6). The IT stores some components of visual memory. We use these functions when we see a classmate outside the classroom and recognize them from our Introduction to Neuroscience class, or when we see a parody of a famous painting and recognize the similarities to the original work. A simple behavioral task to assess visual memory would start by viewing a series of abstract shapes, and when a shape appears that you have already seen, you push on a button. The human capacity for visual memory is massive: After viewing 10,000 images for a few seconds apiece, people were able to identify a previously seen image successfully about 83% of the time.

A bit more specifically, one part of the IT is the fusiform gyrus, which has been previously described in the context of facial recognition. People with prosopagnosia, a visual perceptual disorder affecting the fusiform gyrus, can perceive the different parts of a person’s face, but have a difficult time putting the whole picture together and matching those features to a specific person. For facial recognition to be accurate, there must be some memory that allows for a person to match those facial features with someone they have seen before, which is a memory related process.

The parahippocampal place area (PPA), also found in IT, contributes to visual memories associated with locations and environmental scenes. Imaging studies have demonstrated that activity of the PPA increases specifically when people view place-related images, including scenic landscapes like mountains, man-made structures like campus buildings, or the interiors of rooms, both furnished and completely empty. To serve as control stimuli, viewing faces or objects does not increase the activity of the PPA.

Prefrontal Cortex (PFC)

As part of the frontal lobe, the PFC is involved in high order decision making and personality. In the context of memory, neural circuits in PFC are important for short-term and working memory. Patients with injuries to their prefrontal cortex after stroke, tumors or aneurysm, performed worse on a variety of working memory tasks such as the digit span test. Additionally, people with frontotemporal dementia, a neurodegenerative disorder characterized by a degradation of the frontal lobe, often have difficulty with working memory.

The PFC also has strong projections with the hippocampus, and these circuits are likely also involved in the formation of hippocampal- dependent memories.

Striatum

The striatum is a structure of the basal ganglia, a series of brain structures that contribute to behaviors, such as motor activity and procedural memories. The dorsal striatum likely stores memories involved in habits. Habitual behaviors help us preserve cognitive bandwidth, reducing the “mental energy” that is used during repetitive task performance. The downside of habits is that reliance on habitual responding can limit behavioral flexibility, and cause a person to act in a suboptimal manner, perhaps behaving in a way that led to a positive outcome in a previous set of circumstances without incorporating and evaluating the present circumstances.

Habitual actions are likely related to a variety of neuropsychiatric disorders. Obsessive compulsive disorder (OCD), for example, is characterized by the presence of recurring, intrusive thoughts, which can lead to repetitive actions. Commonly observed is the thought that one’s hands are unclean, which leads to repeated handwashing. A rodent behavioral test of habitual activity is the observation of self-grooming, a natural and healthy series of stereotyped actions that consists of licking the paws and moving them through the fur of the nose, caudally down the body. Mouse models of OCD show excessive self-grooming to the point where they pull their fur out and paw their skin to the point of injury. Drug addiction also involves the striatum. Compulsive drug use is often associated with a series of habitual motor actions that happen before a person experiences the drug effect. For example, in tobacco use disorder, people will perform an orchestrated series of actions, including opening a pack of cigarettes, flicking the lighter, withdrawing the cigarette and taking a deep inhalation. Some of these behaviors are likely stored across striatal circuit. The ventral part of the striatum is involved in  operant conditioning, where we learn to repeat behaviors associated with pleasurable consequences and to avoid those with negative consequences.

Cerebellum

The cerebellum is the phylogenetically ancient structure found posterior and ventral to the cerebrum, and functions generally to help with motor functions. The cerebellum is involved in procedural memories, particularly the performance of motor abilities. Learning new motor skills likely requires changes in the circuit strength of cerebellar neurons.

This list of brain structures involved in memory is certainly not exclusive. For example, the orbitofrontal cortex plays a role in positive emotional memories, and sensory cortices are important for the memories related to the specific stimuli that are processed in those areas. A single memory is likely stored in a neural network that involves several brain areas, much like a mosaic.