Further Understanding the Role of The Hippocampus in the Fields of Depression, Memory and Spatial Awareness
B.Giffney, M.Doody and E.Hussey
Contents
Introduction
The role of the hippocampus is like that of many other parts of the brain. That’s to say still a mystery. Through the years of research and experimentation, only a moderate amount of information has been gained. We know that it plays a function in emotion, by way of it being a part of the limbic system. However further roles have been discovered in the last number of decades. Roles like the hippocampus’s effect in patients suffering from depression or how it has since been discovered that it plays a vital role in memory, particularly long-term memory. Subsequent tests have shown it uses its memory formation aspects as a form of spatial awareness. Throughout this paper, we will discuss our findings and understanding of each of these newly discovered aspects in the title above.
The Role of The Hippocampus in Depression
Introduction
Depression: a life-altering neurological disease of which the cause and physiological workings in the brain continue to baffle both scientists and researchers in the medical field alike. When one thinks of depression and the areas of the brain most associated, the hippocampus does not immediately spring to mind. Continuous, progressive research is being carried out investigating this small but complex structure located in the medial temporal lobe of the brain, with many studies giving the same results. In this essay I will explore the physiological role of the hippocampus in depression and compare the findings in a number of research articles, which draw the same conclusion, that depression causes a reduction in volume of the left hippocampus, a reduction in expression of plasticity-related molecules and a suppression in the generation of new, functional neurons in the hippocampus.
Firstly, I will describe the basic hippocampal circuit, and acknowledge the key structures that I will refer to in this essay. The circuit begins at the dentate gyrus and travels inward along the S-curve of the hippocampus. The Dentate Gyrus is a separate structure, consisting of a tightly packed layer of small granule cells, wrapped around the hippocampus proper. There are a series of Cornu Ammonis areas: CA4 (which underlies the dentate gyrus), CA3, CA2 and CA1, all of which are packed with pyramidal cells. After CA1 is the subiculum. The hippocampus proper refers to the four CA fields. The hippocampal formation refers to the hippocampus proper plus the dentate gyrus plus the subiculum. (Wikipedia, 2019)
Reduction in Volume of the Left Hippocampus
The reduction in the volume of the Left Hippocampus is a common feature in depressed subjects. In Mervaala’s study, the hippocampal volume was investigated in thirty-four patients presenting the criteria for major depression, and the results showed reduced hippocampal volume in the left hippocampus in all subjects, with a trend towards a reduction in the right hippocampus also. There are a number of physiological reasonings for this finding. Firstly, the hippocampal formation is rich in corticoid receptors. The receptors are type I (Mineralocorticoid, MR) and type II (glucocorticoid, GR). (Wikipedia, 2018) These receptors function in the maintenance of basal HPA (hypothalamic-pituitary-adrenal) tone and in the regulation of negative feedback of glucocorticoid release during stress. Cortisol is a glucocorticoid and has a ten times greater affinity for MR’s than for GR’s. Stress evoking the secretion of excessive corticotropin-releasing factor (CRF) from the hypothalamus may contribute to the hippocampal volume loss via glucocorticoid induced neurotoxicity. (Mervaala et al., 2000).Neurotoxicity can alter the activity of the nervous system in ways that can disrupt nerves, thus reducing hippocampal volume.
The second factor to be considered in this volume reduction is BDNF- Brain Derived Neurotropic Factor. It is synthesized in the hippocampus and its synthesis is believed to reduce stress. It does so through a sustained modification of the chromatin structure. (Castrén et al., 2007) This same study hypothesized that an infusion of BDNF into the hippocampus would mimic the action of antidepressants. Neurotropic factors are critical regulators of the formation and plasticity of neuronal networks. It is shown that stress reduces BDNF expression in the hippocampus, the basis of this mechanism of action can be observed when tyrosine phosphorylation of the TrkB receptor occurs, thus activating the phospholipase C gamma signalling. This consequently leads to the phosphorylation of cAMP related binding protein, which is a major factor directing gene expression of plasticity-related molecules. Chromatin remodelling (changes in the histones which wrap around chromosomal DNA) regulates the activity of gene transcription. BDNF can be epigenetically modified at the chromatin level by trauma/stress. (Castrén et al., 2007) It is argued that neurotropic factors are directly involved in hippocampal volume reduction.
Thirdly, hippocampal neurogenesis occurs when new functional neurons are added to the dentate gyrus of the hippocampus, (Sahay, 2011) a decrease in neurogenesis would reduce the volume of the left hippocampus. Investigations also consider alterations in the dendritic, axonal and synaptic components of neurons or in the glial cells of the hippocampal neural network. (Fuchs et al., 2004) In this investigation, tissues of nineteen depressed subjects and twenty-one age-matched psychiatrically healthy control subjects were obtained and the number of glia and neurons per unit volume was estimated with an optical dissector. The results showed a notable difference between control and depressed patients in the thickness of the sections after histological processing and a 17-21% decrease in the average soma size of depressed subjects.
To reiterate Fuchs’ findings, in another study, alterations in grey matter density and decreased hippocampal neurogenesis were found in depressed animal subjects.(Stockmeier et al., 2004) Grey matter, in this case, consists of the cell bodies.
However, despite all of these findings, it remains unclear as to whether the hippocampal volume reduction exists prior to the development of depression or if it is due to recurrent episodes of depression. (Mervaala et al., 2000)
Expression of Plasticity Related Molecules
Expression of Plasticity Related Molecules Neural plasticity is the ability of neurons and neural elements to adapt in response to internal and external signals. Antidepressants induce the expression of plasticity-related proteins, for example, phosphorylated CREB and polysialylated neural cell adhesion molecule in the hippocampus (Wainwright e Galea, 2013), a reduction in the expression of these proteins could lead to depression.
Cell Adhesion Molecules (CAM’s) are proteins usually on the cell surface important in synaptic function, synaptic plasticity and remodelling of neural circuits. NCAM (neural cell adhesion molecules) mediate calcium independent cell to cell interactions and cell extracellular matrix (ECM) interactions. NCAM’s are important in mediating neural plasticity, and one of its most important roles includes glycosylation with polysialic acid (PSA). PSA NCAM regulates cell to cell and ECM interactions during times of plasticity, therefore, selective cleavage of PSA inhibits activity-induced synaptic plasticity, and alters the normal migration and integration of newly generated neurons within the hippocampus (Wainwright et Galea, 2013).
The reductions in neuroplasticity can be mainly attributed to reductions in neurogenesis and the expression of proteins associated with neural plasticity.
Production of New Neurons
Production of New Neurons The production of new neurons in the brain takes place in two places, one of them being the subgranular zone of the hippocampus. The proliferating cells in the subgranular zone of the hippocampus migrate into the granular layer where they give rise to mature neurons. (Fuchs et al., 2004). Stress can suppress the proliferation and survival of these neurons.
https://upload.wikimedia.org/wikipedia/commons/5/59/Hand_drawn_hippocampus.jpg
Conclusion
It is clear from the articles that there is an interconnection between depression and the hippocampus. The dominating effect of depression on the hippocampus is evident in the vast amount of evidence and research articles concerning the reduction in volume of the left hippocampus. In my research, I found the articles by Castrén, Fuchs, Mervaala and Stockmeier to provide the most convincing evidence to reinforce this effect, and it is obvious that the reduced volume is not due to one single physiological process, but it is rather an amalgamation of many, usually stress induced, effects.
Role of the Hippocampus in memory formation and function
I believe there is an agreement and current textbook knowledge which shows that the hippocampus has a function in memory formation and function. This connection has been studied in great detail with the hopes to further our understanding of the human brain and its capacity and mechanism for remembering. However, breakthroughs in this field are rare. Many experiments have been performed with very little progress made. I have read the scientific papers of such experiments and will summarise my findings below.
Introduction to the papers
Through all the papers one common question appeared repeatedly. Which type of memory is the hippocampus associated with? Declarative? Episodic? Semantic? In truth the answer is a little of all of them. In the first and fourth paper listed Vargha-Khadem( V.K. henceforth) and her colleagues studied three young people suffering from anterograde amnesia caused by early-onset hippocampal pathology. (Vargha-Khadem et al., 1997; Tulving and Markowitsch, 1998). What was strange about these three young people was that despite their hippocampal pathology they possessed apparently normal or near-normal intellectual development. So, these three patients had managed to do what many thought impossible with anterograde amnesia, they have managed to learn and retain a lot of declarative information. While V.K. and her colleagues argued for a change in the existing theory based around the hippocampus’ role in declarative and episodic memory, Eldridge and her colleagues tried to focus on the hippocampus’ role in the retrieval of memories(Eldridge et al., 2000). They went about achieving this aim by measuring brain activity during memory retrieval using event-related functional magnetic resonance imaging. Neuroimaging techniques give us a way of measuring activity and patterns of the brain all while the retrieval process takes place. This showed that the hippocampus increased only when retrieval was accompanied by the conscious recollection of the learning episode. They knew it was critical to study how the hippocampus is involved in retrieval processes to understand whether the hippocampus is uniquely involved in episodic memory. Unfortunately, hippocampal patients tend to suffer from a pronounced learning deficit that may obscure the true nature of an additional retrieval deficit. Hence why V.K. study was so unique and could stand to challenge the existing theory of hippocampal function. (Tulving and Markowitsch, 1998; Vargha-Khadem et al., 1997) In my final paper, Fortin and his colleagues discuss the if the hippocampus, which we now know has a role in episodic memory, plays a part in the sequencing of these episodic memories(Fortin, Agster and Eichenbaum, 2002).
Tests performed
Each of the papers performed experiments to support the hypothesises. V.K. performed simple yet concise test differentiating the two forms of memory, declarative and episodic. Before running these tests, she first precisely delineated the underlying brain pathology in each of her three patients. This precise mapping of the brain in early-onset amnesia patients had no previous well-documented reports. (Tulving and Markowitsch, 1998) While V.K.’s paper itself is more concerned with the figures and results( the fact that semantic knowledge had been retained without the use of the hippocampus’s episodic function) of her study(Vargha-Khadem et al., 1997), in Tulving’s review they dive deep into the idea that we need to redefine declarative and episodic memory and the role of the hippocampus in both these memory types (Tulving and Markowitsch, 1998). As mentioned above Eldridge used neuroimaging techniques, however these techniques would show very little results if the brain was not activated. To ensure the right parts of the temporal lobe were activated, subjects were told to memorize each word for a subsequent memory test. Twenty minutes later they presented the subjects with studied and unstudied items. They asked them first to determine whether they had studied the word, and then to classify their memory for the word as episodic or non-episodic. Two buttons were then pressed to categorise the subject into either known/remembered(Eldridge et al., 2000). In Fortin’s work, he was working with an animal model in the form of rats. Since he was working with rats, he could now cause the lesions to the area desired and so see the impairment on the memory of the rodents. The test used tested the capacity of rats to remember the sequential ordering of a series of odours, despite an intact capacity to recognize odours that recently occurred. This test ties excellently into our section about the spatial memory, since all special awareness is based on an animal’s ability to remember the area he/she is in. Take a mouse in a maze, for example, its first run is often the longest because it is unfamiliar with the maze. The more attempts it has the quicker its time becomes due to the brain remembering the sequence of turns required to get to the destination. This exact phenomenon is what Fortin’s experiment was trying to prove. In this experiment Fortin directly compared memory for sequential order of events with memory for the prior occurrence of events independent of their order. (Fortin, Agster and Eichenbaum, 2002)
Conclusions
V.K.’s theory on the role of the hippocampus in declarative and episodic memory counters that advocated by a number of theorists (e.g., Squire and Knowlton, 1995; Squire and Zola, 1996; Cohen et al., 1997). In the end she and her colleagues agree that their findings fit the scheme of memory organization in which episodic and declarative memory are distinct systems. However, she is further proposing that the hippocampus is necessary for episodic but not declarative memory, whereas the surrounding cortical regions are necessary for declarative memory. Her findings are vital because of her patient's unique hippocampal pathology and how her results can incorporate a lot of the novel findings that have been dismissed in previous studies. (Vargha-Khadem et al., 1997; Tulving and Markowitsch, 1998). Eldridge concluded that some previous studies have failed to find activation in the hippocampus during retrieval because during episodic retrieval MR signal increased in the hippocampus, whereas during non-episodic retrieval it decreased. This self-cancellation effect had a huge role in the importance of her findings in disproving many previous papers. It was likely that answers given the K grade (known) may have possessed both episodic and non-episodic memories. If subjects decide in a single step whether an item is an R (remembered) grade they would on average be more likely to use the R grade to signify a strong and a K grade to show a weak response rather than episodic and non-episodic memory. (Eldridge et al., 2000). Finally, Fortin discussed how his results showed the hippocampus has a role in the sequencing of the episodic memories he further stipulated that the hippocampus does not play a role in the recognition of these items that occur in a unique sequence(Fortin, Agster and Eichenbaum, 2002). This conclusion ties again into V.K.’s unique patients as often times they could recall the information but could not recall ever having studied it. (Vargha-Khadem et al., 1997)
The Role of the Hippocampus in Spatial Memory
Introduction
The scientific community agree that the hippocampus plays an essential role in allosteric spatial memory. Many experiments have been carried out in order to attain a greater understanding of the topic. Of those that I read; scientists were trying to determine if the hippocampus has any specific memory functions that differentiate itself from the adjacent cortexes. Shrager and her team wished to test the theory that the hippocampus is especially important with regards to remembering object locations when there is a shift in viewpoint (Shrager et al., 2007). In a second paper, Morris realised that NMDA antagonists had similar effects as hippocampal lesions in terms of spatial learning degradation. (McHugh et al., 1996). These finding led to a chain reaction of questions such as would NMDA-plasticity impair the learning of spatial information? Conventional gene knockout techniques by (Tsien, Huerta and Tonegawa, 1996) proved there was a link between hippocampal synaptic plasticity and spatial learning deficits. Another study which tested the importance of the integrity of the hippocampus in spatial memory was carried out by Broadbent and her team.
Experiments
In Shrager’s experiment patients performed image-memory location tests. They were given time to view the image followed by an eight second delay period followed by the test. Different numbers of images could appear at 21 different locations and during the delay period, the virtual environment rotated the viewpoint between a range of 0 to 140 degrees. Results lacked significance as patients performed reasonably well until the number of images were increased above two. This led me to believe that damage to the hippocampus did not disproportionately reduce memory when there was a shift in spatial viewpoint. Rather, hippocampal damage impaired memory as the memory load increased. Using a multielectrode technique Wilson (Wilson and McNaughton, 1993) monitored place fields in the hippocampus of a freely behaving mouse. Results implied that NMDA receptor-dependent synaptic plasticity is involved in place specificity of individual CA1 pyramidal cells. These results as well as (Tsien, Huerta and Tonegawa, 1996) imply that refined place fields and coordinated firing may be fundamental in spatial learning. Abnormalities were found in the neuronal response during spatial exploration. The firing of CA1 pyramidal cells were preserved in CA1 knocked out mice therefore place field specificity was clearly worsened in comparison to littermate controls. Broadbent and her team tested to see if spatial memory was impaired by hippocampal lesions. (Broadbent, Squire and Clark, 2004). To test this theory, she first had to train the rats to understand a standard water maze with a retractable platform that the rats were trained to escape using. She then varied lesion size and performed the tests over again. In Broadbent’s tests, it was obvious that those with the largest lesions were significantly slower escaping on average. This is clear evidence that there is a direct relationship between spatial memory and the integrity of the hippocampus.
Conclusion
The hippocampal region is not solely responsible for spatial memory. Damage to the hippocampus not only leads to spatial memory impairment but equally effects memory deficits which have no obvious spatial component.
Conclusions
There is strong evidence to suggest that the hippocampus plays a vital role in several neurological to physical processes. The brain structure is linked with depression, where the vast majority of depressed subjects show a reduction in the volume of the left hippocampus, caused by a number of physiological imbalances. Depression also causes a reduction in neural plasticity, by the effect of decreased expression of plasticity-related molecules. And finally, it was concluded that this disease diminishes the production of new neurons in one of the only two places new neurons are produced in the brain- the subgranular zone of the hippocampus. All these physiological occurrences, therefore, must influence the memory of a depressed person in some way. As discussed above the memory function of the hippocampus is vital to the episodic part of memory. Perhaps this is why depressed people often have trouble remembering exact details about the period in which they were suffering. Overall the importance of the hippocampus in memory cannot be stressed enough as it serves huge importance in the sequencing of memories. Without it, we wouldn’t be able to tell apart what we experienced yesterday vs. what we experienced as a child.
From reading several studies based on the hippocampus, it is very apparent that the integrity of the hippocampus plays a central role in allosteric spatial memory function, the episodic memory function and is critical also to the physiological reasons for depression. Furthermore, it has an ideal location in the brain in order to carry out its function in memory and depression because of its ability to communicate with the limbic system and the surrounding cortex.
References
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3) Eldridge, L. L.; Knowlton, B. J.; Furmanski, C. S.; Bookheimer, S. Y. and Engel, S. A. (2000) 'Remembering episodes: a selective role for the hippocampus during retrieval', Nature Neuroscience, 3(11), pp. 1149-1152
4) Fortin, N. J.; Agster, K. L. and Eichenbaum, H. B. (2002) 'Critical role of the hippocampus in memory for sequences of events', Nature Neuroscience, 5(5), pp. 458-462.
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11) Tulving, E. and Markowitsch, H. J. (1998) 'Episodic and declarative memory: Role of the hippocampus', Hippocampus, 8(3), pp. 198-204.
12) Vargha-Khadem, F.; Gadian, D. G.; Watkins, K. E.; Connelly, A.; Van Paesschen, W. and Mishkin, M. (1997) 'Differential Effects of Early Hippocampal Pathology on Episodic and Semantic Memory', Science, 277(5324), pp. 376-380
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