Abstract

The three-layered structure of the hippocampus distinguishes it from the cerebral cortex and makes it an interesting place for neural sciences studies, including in vivo and ex vivo LTP. The physiology of the hippocampus is fascinating, so that its unique regions undergo changes, such as neurogenesis and plasticity throughout life; new neurons form from stem cells in at least two areas in the brain: the hippocampus and the olfactory bulb. Therefore, neurogenesis occurs and contributes to learning and memory. Any reduction in the number of neurons in the hippocampus diminishes at least one type of hippocampal memory formation. These changes are important for learning and memory.

Along with learning and memory, the hippocampus also plays a key role in spatial navigation, emotions, and motor behaviours. Nearly all regions of the hippocampus are densely interconnected with various pathways originating from diverse areas of the brain. These include adenosine, dopaminergic, serotonergic, glutamatergic, GABAergic, noradrenergic, and cholinergic projections, each contributing unique functions to hippocampal processes. Among these, GABAA and glutamate are recognized as key players in long-term potentiation (LTP), as well as in learning and memory. This article provides an overview of hippocampal physiology and pharmacology under normal conditions.

Keywords: Hippocampus; Physiology and Pharmacology; Anatomy; LTP; Learning and Memory; Synaptic Plasticity

Abbreviations:LTD: Long-Term Depression; LTP: Long-Term Potentiation; AD: Alzheimer’s Disease; DG: Dentate Gyrus; CA: Cornu Ammonis

Introduction

The hippocampus, an S-shaped structure in the medial portion of the temporal lobes of the brain [1, 2], is located in the posterior region of the limbic system [2]. Its resemblance to the seahorse encouraged its naming after this sea creature. Over the past century, the hippocampus has been identified as the main area for organizing emotional responses [3], recalling memories [4], and playing a crucial role in learning and memory [5]; however, it is also one of the most vulnerable parts of the brain in disorders like Alzheimer’s disease (AD) [6].

Its relatively simple anatomy and synaptic connections make the hippocampus an ideal model at the forefront of research for neuroscientists, especially electrophysiologists, to study the mechanisms of long-term potentiation (LTP), long-term depression (LTD), and the bases of memory formation. LTP happens as a result of a surge in Ca2+ influx into the presynaptic neuron in reaction to tetanic stimulation. This Ca2+ influx triggers the Ca²⁺/calmodulin-dependent adenylyl cyclase cascade, leading to an increase in cAMP levels [7]. Conversely, LTD represents a reduction in synaptic strength caused by weaker stimulation of presynaptic neurons, accompanied by a modest increase in intracellular Ca2+ concentrations [7]. The current study aims to provide a review of the anatomy, physiology, and pharmacology of the hippocampus under normal conditions.

Hippocampal Anatomy Intrinsic Circuitry

The hippocampal curve and sulcus divide it into the dentate gyrus (DG), surrounded by the Cornu Ammonis (CA) fields, and the subiculum. The subiculum forms the dorsal section of the parahippocampal gyrus [8].

The CA fields, made up of pyramidal cells, are histologically divided into four regions (CA1–CA4), playing a crucial role in the matching and mismatching of obtained information [9, 10].

The DG, the deep area of the hippocampus, functions as a gateway and serves as an input area that receives signals from the entorhinal cortex. It plays a critical role in pattern separation, information processing, and associative memory [11-14]. The entorhinal cortex sends the main cortical inputs to the hippocampus through two pathways; one projects to the subiculum and CA1 (output layer) fields and the other one is the strongest projection to the DG. From the DG, projections extend to the CA3 field via mossy fibers. The CA3 field, in turn, establishes a feedback projection to the DG through excitatory mossy cells and also connects to the CA1 region through the Schaffer collateral pathway. Finally, CA1 sends major signals back to the entorhinal cortex via the subiculum, effectively completing this loop of neural communication [15-19].

The latest examinations have led to new investigations of the CA2 field, which has typically been viewed as a transitional area between the CA1 and CA3 fields. However, it is now evident that the CA2 region is a distinct unit with its specific functions [16, 20, 21].

Other cortical and subcortical connections

Besides the major projections from the entorhinal cortex, the hippocampus receives inputs from the perirhinal and postrhinal cortices, as well as subcortical inputs from structures like the amygdala, raphe nucleus, locus coeruleus, and medial septum. The CA1 and CA3 regions primarily send output signals to the lateral septum. Moreover, CA1 projects to other areas such as the prefrontal cortex, amygdala, and nucleus accumbens [22-25]. Notably, the nucleus accumbens plays a crucial role in nicotine dependency [26-28].

Hippocampal Physiology

The significance of the hippocampus in memory became evident with the discovery of LTP in the 1970s [29, 30]. This understanding was further supported by observations in patients with hippocampal damage, which led to anterograde and retrograde amnesia [31], as well as impairments in implicit memory [31, 32].

The physiology of the hippocampus is fascinating, featuring distinct regions that experience changes like neurogenesis and plasticity throughout a person’s life. These changes play a crucial role in learning and memory [33]; Learning is the acquisition of a variety of information, while memory is the storage and retrieval of that information. Therefore, both processes should be considered as interconnected and complementary.

From a physiological perspective, memory can be divided into two main categories. The first is explicit memory, also known as declarative memory, which is linked to conscious thought and relies on the hippocampus. Explicit memory is divided into semantic memory for facts and episodic memory for events.

The second is implicit memory, or non-declarative memory, which operates outside of conscious awareness and typically does not depend on the hippocampus. Another distinct type of memory is working memory, which temporarily holds information while determining how to process or use it. A well-known example of this is remembering a phone number just long enough to dial it.

Working memory regions maintain connections with the hippocampus. Bilateral lesions in the ventral hippocampus, as well as conditions like Alzheimer’s disease and similar disorders that damage CA1 neurons, result in significant impairments in shortterm memory. Despite such damage, individuals generally retain working and implicit memory. While they lose the ability to form new long-term memories, they can still acquire new skills and preserve older memories. This underscores the critical role of the hippocampus in transforming short-term memories into longterm ones.

Research indicates that the experience-driven growth of new granule cells in the DG of the hippocampus may play a role in learning and memory [7]. However, there is still significant work required to fully elucidate the link between these newly formed cells and memory processing. The hippocampus, with its unique three-layered structure, stands apart from the cerebral cortex and remains a compelling subject of investigation in neural sciences. Techniques such as in vivo and ex vivo LTP studies [34] have proven invaluable in exploring the cellular mechanisms underlying memory formation—processes that ultimately drive learning and memory.

Furthermore, additional findings, such as head direction cells, place cells, and grid cells, demonstrate that the hippocampus plays a pivotal and essential role in memory formation. It offers a remarkable framework that integrates the various cognitive, sensory, and emotional aspects of information [2].

An essential component of hippocampal formation is Shaffer’s Collaterals, which are axon branches originating from CA3 cells and projecting to the CA1 region. These connections are crucial for memory formation. Excitatory glutamatergic projections within these circuits play a key role in supporting neuronal plasticity [35-37].

The hippocampus is not only essential for learning and memory but also plays a crucial role in spatial navigation [38], emotions [3], and even motor behaviours [39]. For functions like spatial navigation and learning and memory, the hippocampus interacts with the neocortex, receiving information from the temporal, parietal, and occipital lobes [40]. When it comes to motor behavior, the hippocampus is part of the ventral striatal loop [41]. Regarding emotional behavior, it forms reciprocal connections with the amygdala and sends projections to the hypothalamus, which subsequently influences the release of adrenocorticotropic hormones [42].

Cellular arrangement and functional organization

A distinguishing feature of the hippocampus is its unidirectional tri-synaptic pathway, beginning in the entorhinal cortex and extending to the DG. From there, the mossy fibers of the DG connect with the pyramidal neurons in the CA3 region, whose axons form the Schaffer collateral fibers, which in turn synapse on the pyramidal neurons of the CA1 region [15-19, 35-37, 43]. Each region of this pathway exhibits a specific cellular arrangement and functional organization. For instance, the principal cells in the CA1 and CA3 regions are pyramidal cells, while in the DG, they are granule cells. These principal cells are excitatory glutamatergic neurons, supported by a significant number of interneurons [35-37, 43].

In addition to their structural and functional differences, these hippocampal areas exhibit varying levels of vulnerability to conditions such as AD, aging, and hypothyroidism [44-46]. They also display distinctive discharge patterns and respond differently to various influences like reward or stress [43, 47].

Notably, due to its capacity for neurogenesis, the DG is more heavily influenced by external factors, including activities like learning and exercise [48, 49].

Neurogenesis

The traditional view that neurons remain constant and do not grow in number after birth has been proven incorrect. Research shows that new neurons are generated throughout life from stem cells, primarily in the hippocampus and the olfactory bulb. This process, known as neurogenesis, is integral to learning and memory functions. A reduction in the number of neurons within the hippocampus can impair at least one category of memory production associated with this region.

Synaptic Plasticity

The history of synaptic discharge can lead to both short-term and long-term changes in synaptic function, allowing the synaptic transmission to be either strengthened or weakened based on past experiences. These alterations play a crucial role in the processes of learning and memory. Such changes can occur at either presynaptic or postsynaptic sites.

LTP refers to a rapid and enduring increase in postsynaptic potential, triggered by an elevation in intracellular Ca2+ following brief, repeated stimulation of the presynaptic neuron. This effect can persist for days and takes place in various regions of the central nervous system. However, it has been extensively studied in the hippocampus through two primary models: 1) LTP at Schaffer collaterals, which is postsynaptic and dependent on NMDA receptors, and 2) mossy fiber LTP, which is presynaptic and operates independently of NMDA receptors.

The phenomenon of synaptic plasticity and its response to various stimuli is a key feature of the hippocampus, differing significantly across its regions, particularly in the DG and CA1 areas [43]. The threshold for long-term potentiation (LTP) induction is notably higher in the DG compared to CA1, requiring stronger stimulation to induce LTP in the DG [50, 51]. For instance, in an avoidance learning model, heightened arousal enhances LTP in the DG but may inhibit LTP in the CA1 region [52]. Similarly, in an AD model, chronic stress suppresses both the early and late phases of LTP in the CA1 region, while leaving the late-phase LTP in the DG unaffected [53, 54].

Long-Term Memory

The encoding process for short-term explicit memory occurs in the hippocampus, while long-term memories are distributed across various regions of the neocortex. These fragments of information are interconnected through long-term changes in synaptic strength, enabling the retrieval of all related details through multiple pathways, cues, or links. Additionally, an emotional element influences whether these memories are perceived as pleasant or unpleasant.

Hippocampal Pharmacology

Nearly all regions of the hippocampus are extensively interconnected with a variety of pathways originating from diverse areas of the brain. These include adenosine, dopaminergic, serotoninergic, glutamatergic, GABAergic, noradrenergic, and cholinergic projections, each playing distinct roles within the hippocampus [55-58]. For example, GABAA subunits and N-Methyl-D-aspartate (NMDA) receptors are recognized as critical for LTP [59, 60] as well as learning and memory [61]. Notably, the hippocampus, particularly the CA1 layer, contains the highest concentration of NMDA receptors in the brain [61]. As a type of glutamate receptor, NMDA receptors play a key role in facilitating LTP [60].

The hippocampus, due to its unique physiology and high concentrations of NMDA receptors, exhibits significant plasticity essential for learning and memory. However, it is also highly vulnerable; damage to hippocampal projections or abnormalities in NMDA receptors can result in disorders such as schizophrenia and AD [62, 63]. These disruptions can impair the hippocampus’s primary functions, including its critical roles in learning and memory [64, 65]. Neurodegenerative diseases often affect cognitive functions, particularly memory processes. In conditions such as AD, the capacity to remember can be significantly diminished due to disruptions in neuronal communication. Pathological changes occur in several neurotransmitter systems in AD, including glutamatergic, serotonergic, noradrenergic, and cholinergic systems [66]. This highlights the critical role that various neurotransmitters play in memory formation, with different transmitter systems contributing uniquely to mnemonic functions.

Neurotransmitter interaction with LTP

As discussed in previous sections, LTP, a key candidate for understanding learning and memory, appears to rely significantly on the role of glutamatergic receptors [59, 60]. Both NMDA and AMPA receptors are crucial to the LTP process: NMDA receptors contribute to the induction of LTP, while AMPA receptors are central to its expression. Additionally, GABA may play a role in LTP mechanisms, as blocking GABAergic receptors with antagonists tends to facilitate LTP induction. This indicates that LTP is in fluenced by both the excitatory effects of glutamatergic systems and the inhibitory action of GABAergic systems. Consequently, these neurotransmitters are essential for learning and memory processes. Moreover, LTP may also be modulated by other neurotransmitter systems, including dopaminergic, cholinergic, serotonergic, and norepinephrinergic systems [66]. Dopaminergic projections appear to play a role in spatial learning [67] and motivational processes [68], while cholinergic projections are linked to attentional regulation and cognitive performance [69]. Meanwhile, serotonergic projections have a significant impact on emotional processes [70]. Although many neurotransmitter systems contribute to learning and memory, glutamate, GABA, acetylcholine, and dopamine exhibit stronger effects, with glutamate serving as the primary neurotransmitter driving learning and memory functions. [66].

Conclusion

The hippocampus’s S-shaped structure makes it an excellent model in neuroscience research. Besides its unique anatomy, the hippocampus acts as a central hub with extensive connections to nearly every part of the brain. It is crucial for learning and memory and plays an important role in spatial navigation, emotional regulation, and even motor behaviors.

The various regions of the hippocampus are intricately interconnected through numerous pathways originating from diverse brain areas. These include adenosine, dopaminergic, serotonergic, glutamatergic, GABAergic, noradrenergic, and cholinergic systems, each contributing uniquely to hippocampal function.

Despite its essential role, the hippocampus is particularly vulnerable. Damage to its projections or abnormalities in NMDA receptors can lead to conditions like schizophrenia and AD. Such disruptions impair the hippocampus’s core functions, greatly impacting learning, memory, and related processes.

This review offers a comprehensive overview of the key aspects of the physiology, pharmacology, anatomy, and pathophysiology of the hippocampus. Exploring these connections more deeply could lead to new therapeutic strategies for neurodegenerative diseases and help address impairments in learning and memory.