Studying The Hippocampus

If you are interested in studying the roles of the hippocampus in the behaving animal, how do you even begin to go about it? One approach is to remove the hippocampus or inactivate it and assess the cognitive and behavioral consequences of this experimental manipulation. These types of studies were the first to lead to an appreciation of the role of the hippocampus in memory consolidation (reviewed in reference 1). In fact, studies in a human patient, known as patient H.M., were breakthrough studies that led to the appreciation of the importance of the hippocampus in converting a short-lived memory into a long-lasting one (2). We will discuss this aspect of hippocampal function in the last section of the chapter.

A second approach to studying hip-pocampal function is quite different. If you want to know what is going on in the hippocampus of an animal that is learning, why not stick an electrode in its hippocampus and directly monitor the cellular firing pattern? This type of approach has been exploited to great effect of late, and in the next section we will talk about new and important insights into the role of the

Entorhinal Cortex Anatomy
FIGURE 2 Hippocampal connectivity in the CNS. Illustration of the pathway from sensory perceiving regions of the cortex through the perirhinal and entorhinal cortices to the hippocampal formation. Figure adapted with permission from Squire and Lindenlaub (39).

hippocampus in the behaving animal that have been generated using these techniques.

A. Hippocampal Anatomy

First, an anatomical overview is helpful concerning the hippocampal structure, the inputs and outputs of the hippocampus, and the anatomy of the hippocampal formation and related structures in the context of the brain (see Figure 2). The hippocampus receives direct or indirect inputs from all the sensory areas of the cortex including the areas of the cortex involved in late stages of visual information processing, the auditory cortex, and the somatosensory cortex. The hippocampus also receives fairly direct input from the olfactory system via the olfactory bulb. Sensory information of these various sorts is funneled down to the hippocampus via the perirhinal and entorhinal cortices; these are the cortical areas in the immediate anatomical vicinity of the hippocampus near the rhinal fissure in the temporal lobe.

The outputs of the perirhinal and entorhinal cortices then project to the dentate gyrus and the hippocampus proper (these two are referred to jointly as the hippocampal formation). The hippocampus proper is also known in old-style anatomical nomenclature as Cornu Ammonis (Ammon's Horn, after the ram's horn-sporting Greek god) because of its shape. Indeed hippocampus is Greek for sea horse, which is a term coined by anatomists to describe the overall shape of the anatomical structure. The Cornu Ammonis terminology leads to four anatomical subdivisions of the hippocampus: areas CA1, CA2, CA3, and CA4, CA1 and CA3 being the largest and most easily identified. The principal neurons in the CA regions are called pyramidal neurons because of their shape—they comprise about 90% of all the neurons in the CA regions of the hippocam-pal formation. The output neurons of the hippocampus are the CA1 pyramidal neurons—their axons are glutamatergic, and information leaves the hippocampus proper via these axons. The axons of CA1 neurons project back to the entorhinal cortex as well as other structures (see Figure 3). The hippocampus also receives a number of relatively diffuse modulatory projections from various areas of the brain stem. These projections include axon terminals releasing norepinephrine (NE), acetylcholine (ACh), and 5-hydroxytryptamine (5HT, also known as serotonin).

We will return to the synaptic structure of the hippocampus in more detail in the next chapter. For now, suffice it to say that the hippocampus proper, comprising areas CA1-4, plus the dentate gyrus form one functional and anatomical unit involved in information processing and memory consolidation. Exactly how this happens is still mysterious, but current ideas about the cellular and molecular basis of this processing are, of course, the focus of this book.

Information goes out of the hippocampus and ultimately back up into the cortex, backtracking its way once again through the entorhinal and perirhinal cortices. I emphasize this because it is important to remember that these cortical areas immediately adjacent to the hippocampal formation are functionally an extension of the hippocampus (and vice versa). By and large, nothing gets into or out of the hippocampus without passing through the neurons in the entorhinal and perirhi-nal cortex. The point is that throughout the literature (and this book) there are many references to "hippocampus-dependent" processes. These processes might equally well be described as entorhinal cortex-dependent or perirhinal cortex-dependent. The hippocampal formation and its adjacent cortical brethren function in unison to execute the sophisticated cognitive and memory processing that is detailed here.

FIGURE 3 Hippocampal intrinsic circuit and output pathways. Schematic and illustration of the principal pathway through the hippocampus. (A) Schematic of the structures through which the sensory signal travels within the hippocampal formation. (B) A more realistic drawing of these structures (from reference 39 with permission). (C) The signaling that occurs in the area CA1 of the hippocampus, focusing on the cellular connections.

FIGURE 3 Hippocampal intrinsic circuit and output pathways. Schematic and illustration of the principal pathway through the hippocampus. (A) Schematic of the structures through which the sensory signal travels within the hippocampal formation. (B) A more realistic drawing of these structures (from reference 39 with permission). (C) The signaling that occurs in the area CA1 of the hippocampus, focusing on the cellular connections.

III. HIPPOCAMPAL FUNCTION IN COGNITION: THE HIPPOCAMPUS SERVES A ROLE IN INFORMATION PROCESSING—SPACE, TIME, AND RELATIONSHIPS

As just described, the roles of the hippocampus and associated cortices appear to be at least twofold. One role is to process information of a wide variety of sorts, which we will discuss in this section. The second general function, to serve to download information into the cortex for storage in a long-term fashion, we will deal with in the final section of this chapter.

The types of information that the hippocampus deals with, at least as a first approximation, can be divided into three different categories. First, the hippocampus deals with space (e.g., it is known to be involved in processing spatial information as described in the last chapter where we talked about hippocampus-dependent maze learning). Second, the hippocampus deals with time (e.g., with trace associative conditioning). Animals can learn associations that have no intervening time period between CS and US just fine without a hippocampus. However, introducing a delay period between the presentation of the CS and the presentation of the US brings the hippocampus into play. Thus, the hippocampus appears to be critical for allowing the animal to make an association between two stimuli separated in time. Finally, complex associations are hippocampus-dependent; the hippocampus is involved in an animal learning complex contingencies. For example, one specific type of learning of this sort that we will return to later is an animal learning how to predict whether or not a container labeled with a specific scent contains a hidden food reward, depending on recent experience. Learning these types of complicated associations and contingencies brings the hippocampus into play.

In the following sections we address specific examples for each of these categories, illustrating the categories with specific examples from the literature.

A. Space

When an animal is learning about spatial relationships and positions, it utilizes its hippocampus. Specific examples that we talked about in the last chapter include learning that a hidden platform is in a specific place (Morris water maze learning), learning that a specific place is a bad place (contextual fear conditioning), learning that one place is different from another (context discrimination), and learning the order of left/right turns to take in order to navigate a maze (e.g., the more complicated Lashley mazes).

What happens in the hippocampus when an animal is placed in a novel environment and learns about that environment? This is a question that has intrigued neuro-scientists for decades, and many beautiful studies over the years have given us nice insights into a number of specific cellular phenomena that occur in the hippocampus when an animal is exploring and learning about a new environment. Most of these studies have used direct electrical recording of hippocampal electrical activity during exploration of a new environment.

Early studies in this area used electroen-cephalographic (EEG) recordings. EEG recording techniques allow the monitoring of the electrical activity of fairly large populations of cells, by monitoring the mild electric current that flows between and among active neurons as they fire, owing to the influx and efflux of cellular ions. Because EEG recording monitors populations of neurons, the technique is best at detecting the synchronous firing of groups of neurons.

Pioneering EEG studies identified and defined rhythmic firing in the hippocampus when an animal is exploring a novel environment (3). One pronounced example of this that has received much attention is rhythmic firing at the 4-8 Hz (4-8 per second) rate in rodent hippocampus. This type of rhythmic firing around the 5-Hz range is referred to as theta frequency firing, or more commonly as the theta rhythm (see Figure 4). The theta rhythm occurs during locomotion and exploration of a new environment, and many experiments have linked the theta rhythm firing with various spatial learning tasks. These initial studies indicated that specific patterns of neuronal firing in the hippocampus are

Electroencephalography Health Teaching

FIGURE 4 Theta pattern in hippocampal EEG. In this EEG study, electrodes were implanted to monitor the aggregate electrical activity in a population of neurons during exploration behavior. (A) Plan view of the testing room (5.5 m x 9.1 m). Contents: 1, circular maze; 2, elevated ventilating duct; 3, table; 4, animal cages; 5, test console, 6 door; 7, sink; 8, cabinet. Overhead fluorescent lights provide 330 lumen/m2 of illumination at the level of the maze. (B) Recordings obtained during: 1, voluntary movement; 2, REM sleep; 3, still-alert; 4, slow-wave sleep. The recordings before and after a medial septal lesion was made which eliminated theta rhythm were from the same electrode. Time and voltage calibration: 1 second and 500 ^V. Data and figure reproduced with permission from Winson (3). Copyright 1978 American Association for the Advancement of Science.

correlated with spatial and contextual learning in animals.

But what is happening at the level of the firing of individual neurons? For example, suppose you put an animal in an open round field with visual cues in specific places and allow it to learn about its environment. What happens to the firing patterns of its hippocampal neurons? In classic studies, O'Keefe and Dostrovsky identified "place" cells in the hippocampus (4-6). In these experiments, the investigators recorded cell firing within the hippocampus by using implanted extracellular electrodes that could monitor the firing of single cells, referred to as single "units." Recording from neurons in the dorsal hippocampus, O'Keefe and Dostrovsky

FIGURE 5 Place Cell firing patterns. (A) In the early place cell firing report from O'Keefe and Dostrovsky (4), place cells only fired in position A as shown in top diagram. (B) Histogram of firing at each location in the diagram and raw firing patterns during periods marked 1 and 2 in the histogram. Figure reproduced from O'Keefe and Dostrovsky (4). Copyright 1971, with permission from Elsevier Science.

FIGURE 5 Place Cell firing patterns. (A) In the early place cell firing report from O'Keefe and Dostrovsky (4), place cells only fired in position A as shown in top diagram. (B) Histogram of firing at each location in the diagram and raw firing patterns during periods marked 1 and 2 in the histogram. Figure reproduced from O'Keefe and Dostrovsky (4). Copyright 1971, with permission from Elsevier Science.

discovered cells in the freely moving rat that fired only in a specific location within an open field or maze. They referred to these cells as "place cells" and coined the additional nomenclature of "place field" to describe the specific location in the environment where the cell selectively fires (see Figure 5).

Although place cells fire in a way that is highly correlated with the animal's position, these cells fire predominantly when the animal is moving in only one direction (Figure 6). The firing fields are very stable over days and months once established, and place fields are established reasonably quickly (see references 7 and 8), on the order of a few minutes to 1-2 hours (keep in mind that some consolidation process is likely involved). A given place cell can have more than one place field within an apparatus or in two apparati; in other words, a place cell is not exclusively linked to a specific location but may be called upon in connection with one location in one environment and in connection with another location in another environment.

What are place cells? Place cells are hip-pocampal pyramidal neurons. The "unit" firing recorded in these early studies was a manifestation of action potential firing in pyramidal neurons in the CA regions of the hippocampus. We will return to these cells and their synaptic and biophysical properties in greater detail in the next two chapters.

The firing pattern is not absolute but relative; for example, place cell firing depends on the animal's perception of visual cues. This can be demonstrated fairly simply by rotating the cues clockwise or counterclockwise between testing trials for a given animal but keeping their position relative to each other constant. When the cues are rotated the place field for a given place cell stays constant in relation to the cues (see Figure 7) but is independent of the animal's absolute location. This experimental result eliminates the simplest explanation for place fields—the rat is not like a

Visual Perception Direction Example

FIGURE 6 Direction selectivity in place cell firing. Typical directional "place fields" exhibited by pyramidal cells while rats move about the radial eight-arm maze. Arms are represented as pulled away from center to facilitate viewing. Spatial firing rates are broken down according to radial direction of motion (open and filled histograms represend outward and inward, respectively). Although, in extremely simplified visual environments, hippocampal cells are much more poorly directionally tuned, in most situations firing in the direction opposite to the preferred one is rarely significantly different from background. Data, figure, and legend reproduced with permission from McNaughton, Chen, and Markus (38).

FIGURE 6 Direction selectivity in place cell firing. Typical directional "place fields" exhibited by pyramidal cells while rats move about the radial eight-arm maze. Arms are represented as pulled away from center to facilitate viewing. Spatial firing rates are broken down according to radial direction of motion (open and filled histograms represend outward and inward, respectively). Although, in extremely simplified visual environments, hippocampal cells are much more poorly directionally tuned, in most situations firing in the direction opposite to the preferred one is rarely significantly different from background. Data, figure, and legend reproduced with permission from McNaughton, Chen, and Markus (38).

FIGURE 7 Place cells follow rotation of visual cues. Diagram of four-arm radial maze set-up. In this test, the maze remains stationary while the visual cues on the walls are rotated 90° clockwise. When the animal is placed in the first set-up the place field is in the arm closest to the cue marked B (the western arm before the rotation). When the cues are rotated, the place field is again in the arm closest to the cue marked B (the northern arm after the rotation). This indicates that the place field is determined by the animal's relationship to the distal visual cues, not the animal's absolute location in the room.

FIGURE 7 Place cells follow rotation of visual cues. Diagram of four-arm radial maze set-up. In this test, the maze remains stationary while the visual cues on the walls are rotated 90° clockwise. When the animal is placed in the first set-up the place field is in the arm closest to the cue marked B (the western arm before the rotation). When the cues are rotated, the place field is again in the arm closest to the cue marked B (the northern arm after the rotation). This indicates that the place field is determined by the animal's relationship to the distal visual cues, not the animal's absolute location in the room.

homing pigeon that can reference the earth's magnetic field for navigation.

But the rotated cues experiment has a much greater implication. Place cell firing is an example of cognition. The animal exhibits a specific cellular firing pattern in its hippocampus that depends upon its perception of the environment. The place cell firing is not dependent whatsoever on absolute position in space—it is dependent on the animal's perceived position, based on its interpretation of visual and other cues in the environment.

The place field is somewhat of an abstraction, in fact (9, 10). Suppose that you train an animal in a small circular chamber and allow place fields to develop. If you place the same animal in a much larger round chamber with the same relative visual cues, the place field stays constant relative to the cues, at least for a subset of place cells (see Figure 8). To me this is a mind-boggling example of cognitive processing—a direct demonstration that a cellular firing pattern can reflect a generalized construct, an abstract representation of the animal's environment.

Thus, place fields are manifest as a burst of action potential firing in a CA1 pyramidal neuron when an animal enters a perceived spatial location. Or, stated more precisely, place fields are manifest as a burst of action potentials when an animal enters what it perceives to be a particular spatial location. However, it is critically important to keep in mind that the ordering of this sentence may be exactly reversed. It is an equally valid interpretation, because the data are based on correlation, that the burst of action potential firing leads to the animal perceiving itself as being in a certain place. In other words, we might equally well say that an animal perceives itself to be in a particular location whenever a set of hippocampal place cells fires a burst of action potentials. As we learn more about the hippocampus, it will hopefully become more clear whether the hippocampus is "upstream" of spatial perception or "downstream" of spatial perception. In the limit we may find that it is exactly in the middle of spatial perception, (i.e., that place cell firing is the mechanism of spatial perception).

FIGURE 8 Place cells fire in a corresponding location in larger round chamber. Place field in original (left) and larger (right) circular open field is recorded from a hippocampal neuron of a rat searching for food. The larger open field maintains the same orientation in relation to the visual cue (black arc), which is the same size relative to the chamber as in the smaller version. The place field recorded from the rat is shown with black squares and was recorded first in the small chamber and then in the large chamber. The place fields are in the same position relative to the visual cue in each chamber, and also the place field is enlarged in the larger chamber. Data and figure reproduced with permission from Muller and Kubie (9).

FIGURE 8 Place cells fire in a corresponding location in larger round chamber. Place field in original (left) and larger (right) circular open field is recorded from a hippocampal neuron of a rat searching for food. The larger open field maintains the same orientation in relation to the visual cue (black arc), which is the same size relative to the chamber as in the smaller version. The place field recorded from the rat is shown with black squares and was recorded first in the small chamber and then in the large chamber. The place fields are in the same position relative to the visual cue in each chamber, and also the place field is enlarged in the larger chamber. Data and figure reproduced with permission from Muller and Kubie (9).

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