The taiep rat originated from a spontaneous mutation in a colony of Sprague-Dawley rats, whose phenotype is inherited as an autosomal recessive trait. The mutant taiep rat shows hypomyelination and demyelination of the central nervous system (CNS) and has been considered a chronic animal model of multiple sclerosis and tubulinopathies. Unlike taiep rats, heterozygous rats for the mutation (+/-), referred to as carriers, have not been widely studied. Thus, the objective of the present study was to examine the dendritic arborization and dendritic spine density of CA1 and CA3 pyramidal neurons of taiep mutation carriers. We evaluated the following groups: Sprague-Dawley rats as a control (SD), mutation carriers (Carrier), and taiep rats (taiep). The brains of the animals were processed using the Golgi-Cox technique to analyze the basilar and apical dendritic arborization and dendritic spine density of CA1 and CA3 pyramidal neurons. We observed a decrease in dendritic arborization in the basilar arbors of dorsal hippocampal CA1 and CA3 pyramidal neurons in both carrier and taiep adult rats, as well as a decrease in dendritic arborization in the apical arbors of CA3 neurons in carrier rats. Moreover, dendritic spine density was reduced in CA1 neurons in both rats. These results show that even when rats are mutation carriers, they exhibit alterations in the dendritic arborization of dorsal hippocampal neurons similar to those of taiep rats.

This introduction is for the second installment of the special issue on Scientific Histories of Hippocampal Research, with 13 new articles. Part 2 adds to the 24 articles in Part 1, and we expect a third installment in the future. The different parts of this special issue contain articles from authors directly involved in pioneering research on the hippocampus ranging from electrophysiological recordings of neuronal activity to analyses of cellular mechanisms for synaptic plasticity, to behavioral studies of the effects of hippocampal lesions. The authors were specifically invited to provide first person historical descriptions of important research and discoveries concerning hippocampal function, and were encouraged to include information about how their background and training influenced their research. In this introduction to Part 2, we will briefly review some of the main themes discussed in Part 2, which builds on many of the same themes as the articles in Part 1.

ABSTRACTObject recognition memory (ORM) plays a key role in identifying familiar items and encoding episodic information. ORM consolidation depends on β‐adrenergic receptor (βAR) signaling and is associated with increased BDNF expression in the dorsal hippocampus. Although hippocampal activation of cannabinoid type‐1 receptors (CB1Rs) is known to impair ORM consolidation, the mechanisms underlying this effect remain unclear. In this study, we used the novel object recognition task to examine the interaction between CB1Rs and βARs during ORM consolidation in adult male Wistar rats. Intra‐dorsal CA1 infusion of the CB1R agonist ACEA, the βAR antagonist propranolol, or the PKA inhibitor myristoylated PKI14–22, administered 5‐min post‐training, impaired ORM consolidation. Notably, co‐administration of the PKA activator 8Br‐cAMP or the βAR agonist isoproterenol reversed ACEA‐induced amnesia. In contrast, the CB1R inverse agonist AM251 failed to reverse propranolol‐induced amnesia, which was instead rescued by recombinant BDNF infusion into the hippocampus 120‐min post‐training. These findings suggest that hippocampal CB1Rs regulate ORM consolidation by acting upstream of βARs via a signaling cascade involving PKA activation and BDNF expression.

ABSTRACTHippocampal subfields differentially develop and age, and they vary in vulnerability to neurodegenerative diseases. Innovation in high‐resolution imaging has accelerated clinical research on human hippocampal subfields, but substantial differences in segmentation protocols impede comparisons of results across laboratories. The Hippocampal Subfields Group (HSG) is an international organization seeking to address this issue by developing a histologically valid, reliable, and freely available segmentation protocol for high‐resolution T2‐weighted 3 T MRI (http://www.hippocampalsubfields.com). Here, we report the first portion of the protocol focused on subfields in the hippocampal body; protocols for the head and tail are in development. The body protocol includes definitions of the internal boundaries between subiculum, Cornu Ammonis (CA) 1–3 subfields, and dentate gyrus, in addition to the external boundaries of the hippocampus apart from surrounding white matter and cerebrospinal fluid. The segmentation protocol is based on a novel histological reference dataset labeled by multiple expert neuroanatomists. With broad participation of the research community, we voted on the segmentation protocol via an online survey, which included detailed protocol information, feasibility testing, demonstration videos, example segmentations, and labeled histology. All boundary definitions were rated as having high clarity and reached consensus agreement by Delphi procedure. The harmonized body protocol yielded high inter‐ and intra‐rater reliability. In the present paper we report the procedures to develop and test the protocol, as well as the detailed procedures for manual segmentation using the harmonized protocol. The harmonized protocol will significantly facilitate cross‐study comparisons and provide increased insight into the structure and function of hippocampal subfields across the lifespan and in neurodegenerative diseases.

ABSTRACTEvidence from rodents has revealed that the hippocampus processes information in a graded manner along its long‐axis, with anterior regions encoding coarse information and posterior regions encoding fine‐grained information. During navigation tasks with humans, similar patterns have been shown, with granularity of representation and rate of signal varying along the long‐axis. However, the stability of these signals and their relationship to navigational performance remain unclear. In this study, we conducted a 2‐week training program where 26 participants (6 M; 20 F) learned to navigate through a novel city environment. We investigated inter‐voxel similarity (IVS; a measure of representational granularity) and temporal auto‐correlation (a measure of signal change) in the hippocampus. Specifically, we examined how these signals were influenced by navigational ability (stronger vs. weaker spatial learners), training session, and navigational dynamics. Our results suggested that stronger learners tended to exhibit an anterior–posterior distinction in IVS in the right hippocampus, whereas weaker learners showed less pronounced patterns. Additionally, lower general IVS levels in the hippocampus were linked to better early learning. These findings suggest that signal complexity in the hippocampus may play a role in successful navigation and that efficient organization of scales of representation could be beneficial for navigation.

This article is a personal history of the background, ideas, and motivations behind the major discoveries from my lab in the past 27 years. Tracing the main themes back to my training as a graduate student and a postdoc, I discuss how all of our work has been influenced by a desire to use anatomical and computational literature to inspire and constrain the experimental questions we have addressed. The backstory of two fundamental discoveries made in the early days on my independent research program are described: (a) differences between DG, CA3, and CA1 population dynamics in relation to computational theories of pattern separation and pattern completion and (b) differences in the types of information conveyed to the hippocampus from its lateral and medial entorhinal cortex inputs. Also described are how these initial findings set the foundation for numerous subsequent discoveries as we followed the data from one experiment to the next, with the goals of understanding how information is represented and transformed through the hippocampal formation in support of spatial learning and episodic memory.

Relational memory, the ability to flexibly encode and retrieve associations among distinct elements, is critically dependent on the hippocampus and declines with age in humans. The Transverse Patterning (TP) task is designed to probe relational memory by requiring learning of hierarchical, circular stimulus relationships (e.g., A+ B-, B+ C-, C+ A-), a structure akin to rock-paper-scissors. In humans, TP performance is reliably impaired by hippocampal damage and aging. In non-human primates, however, findings have been inconsistent, with some studies demonstrating clear hippocampal dependence, while others report no impairment or even improvements following hippocampal lesions. This raises the possibility that species differences in cognitive strategy use may underlie these divergent outcomes. We hypothesized that non-human primates rely on an elemental learning strategy, solving problems through simple stimulus-response associations, rather than a configural strategy, which requires integrating multiple stimulus relationships into a higher-order relational structure supported by the hippocampus. To test this, we trained young and aged common marmosets (Callithrix jacchus) on the TP task and several control tasks designed to isolate elemental versus configural learning. Marmosets successfully acquired reward contingencies for individual stimulus pairs but failed when success required integrating all three stimulus relationships. In contrast, all animals readily acquired control tasks solvable via simple stimulus-response associations. Notably, there was no evidence of age-related impairment on TP or control task performance. Given the early vulnerability of the hippocampus to aging and the relative preservation of striatal systems, this pattern further supports the conclusion that marmosets rely on a habit-based learning strategy that is poorly suited to relational demands. These findings suggest that humans and non-human primates may approach the same tasks using different cognitive strategies. This has critical implications for interpreting cross-species differences in memory performance and highlights the need to validate which neural systems a task engages in each species before using it as a translational model of hippocampal function or cognitive aging.

ABSTRACTTraumatic brain injury (TBI) is a leading cause of long‐term disability, with limited effective treatment options. A key factor of TBI pathophysiology is neuroinflammation, which can involve the activation of the nucleotide‐binding domain leucine‐rich repeat protein 3 (NLRP3) inflammasome. Aberrant inflammation following injury has the ability to reduce the capacity to induce long‐term changes in synaptic plasticity, a leading mechanism for the development of learning and memory deficits following injury. This study investigated the potential of a novel NLRP3 inhibitor, AMS‐17, to mitigate synaptic plasticity deficits following mild TBI (mTBI) in mice. Adult C57Bl/6 mice were subjected to mTBI or a sham injury, and hippocampal slices were then prepared for field electrophysiological recordings in the medial perforant pathway of the dentate gyrus. We found that mTBI induced deficits in long‐term potentiation that were not immediate at 2 h post‐injury but developed by 3 days post‐injury. We next incubated slices in AMS‐17 or a control solution prior to electrophysiological recordings. Here we found that incubation with AMS‐17 rescued these LTP deficits, bringing them to levels observed in sham‐injured controls. Importantly, AMS‐17 did not affect the capacity to induce LTP in sham‐injured mice. These findings suggest that targeting the NLRP3 inflammasome may offer a promising therapeutic strategy to reduce learning and memory impairments following mTBI. Further studies are needed to determine the optimal therapeutic window and long‐term efficacy of AMS‐17 in mTBI.

While the hippocampus has intrigued generations of neuroscientists for its contributions to cognitive and emotional processing, functional specialization along its longitudinal axis confers particular importance to the ventral hippocampus (vHPC) in affective regulation under normal and pathological conditions. In particular, vHPC is extensively linked to the encoding, expression, and extinction of fear memories, which mediate behavioral adaptation to environmental threats. Despite decades of research, however, many questions remain about precisely what is encoded among specific populations of vHPC neurons and what brain systems cooperate in processing this information during fear regulation. Furthermore, as insights accumulate into the function of discrete afferent projections of vHPC, an important area of focus is how vHPC circuitry might be organized to support different output patterns through synaptic integration. Here, we summarize the current understanding of these issues based on contemporary circuit-based approaches and highlight potential clues to the anatomical and functional organization of synaptic networks that may help reconceptualize vHPC as a system of interacting modules.