Action potentials, the primary information units of the nervous system, are usually generated at the axon initial segment (AIS). Changes in the length and position of the AIS are associated with alterations in neuronal excitability but there is only limited information about the baseline structural variability of the AIS. This work provides a comprehensive atlas of the diversity of proximal cell geometries across all anatomical axes of the murine hippocampus, encompassing dorsal-ventral, superficial-deep, and proximal-distal regions. We analyzed the morphology of 3,936 hippocampal pyramidal neurons in 12 animals of both sexes, focusing on AIS length, position, and their association with proximal cellular features such as the soma and dendritic geometries. Notably, neurons with axon-carrying dendrites were significantly more common in ventral compared to dorsal hippocampal areas, suggesting a functional adaptation to regional demands. Validation of this finding in human samples confirms the translational relevance of our murine model. We employed NEURON simulations to assess the functional implications of this variability. Here, variation in proximal geometry only minimally contributed to neuronal homeostasis, but instead increased heterogeneity of response patterns across neurons.

Adaptive behavior depends on the ability to predict specific events, particularly those related to rewards. Armed with such associative information, we can infer the current value of predicted rewards based on changing circumstances and desires. To support this ability, neural systems must represent both the value and identity of predicted rewards, and these representations must be updated when they change. Here we tested whether prediction error signaling of dopamine neurons depends on two areas known to represent the specifics of rewarding events, the HC and OFC. We monitored the spiking activity of dopamine neurons in rat VTA during changes in the number or flavor of expected rewards designed to induce errors in the prediction of reward value or reward identity, respectively. In control animals, dopamine neurons registered both error types, transiently increasing firing to additional drops of reward or changes in reward flavor. These canonical firing signatures of value and identity prediction errors were significantly disrupted in rats with ipsilateral neurotoxic lesions of either HC or OFC. Specifically, HC lesions caused a failure to register either type of prediction error, whereas OFC lesions caused persistent signaling of identity prediction errors and much more subtle effects on signaling of value errors. These results demonstrate that HC and OFC contribute distinct types of information to the computation of prediction errors signaled by dopaminergic neurons.

The hippocampal formation is central for the learning and consolidation of spatial memories. While it is known that the high-frequency oscillations, called sharp wave ripples, play a critical role for memory processes, it is unclear if they interact with the memory engram and spatial engram cells. Here we identify the effect of these oscillations on engram cells as mice explored two environments over several days. We found that both principal cells and interneurons are part of the cfos-tagged engram. cfos-tagged principal cells, place cells and interneurons are highly reactivated by SWRs, whereas none of the negatively SWR-modulated cells are part of the engram. Together, our findings reveal a critical link between cellular and network mechanisms for memory formation and imply that interneurons play a key role in it.

Nested sleep oscillations, emerging from asynchronous states in coordinated bursts, are critical for memory consolidation. Whether these bursts emerge intrinsically or from an underlying rhythm is unknown. Here, we show a previously undescribed respiratory-driven oscillation in the human hippocampus that couples with cardinal sleep oscillations. Further, breathing promotes nesting of ripples in slow oscillations, together suggesting that respiration acts as an intrinsic rhythm to coordinate synchronization of sleep oscillations, providing a unique framework to characterize sleep-related respiratory and memory processes.

The rodent hippocampal local field potential is dominated by 6-12 Hz theta oscillations during active behaviour that are strongly implicated in spatial coding and memory function across species. Invasive electrophysiology in both rodents and humans has shown increases in hippocampal theta power immediately before the onset of translational movement that persists throughout subsequent motion, and the magnitude of this increase correlates with the distance subsequently travelled. Using non-invasive magnetoencephalography (MEG) and an abstract navigation task, we observed increased theta power during both spatial planning and subsequent navigation. Importantly, theta power in the right hippocampus covaried with subsequent path distance during planning, only when participants were aware of the distance to their goal. During subsequent navigation, hippocampal theta power decreased dynamically as participants approached the goal, only when they were aware of how far they still needed to travel. In addition, theta phase during navigation modulated 70-140 Hz fast gamma amplitude in the entorhinal cortex while traversing novel paths; and 30-70 Hz slow gamma amplitude in the right hippocampus while traversing previously experienced paths. In both cases, theta-gamma phase-amplitude coupling increased with proximity to the goal during navigation, consistent with the hypothesis that sequences of upcoming locations were represented by gamma bursts occurring at successive theta phases. In sum, these findings are consistent with the proposed role of hippocampal theta oscillation in flexible planning and goal-directed spatial navigation across mammalian species.

The adaptation to the daily 24-h light-dark cycle is ubiquitous across animal species and is crucial for maintaining fitness. This free-running cycle occurs innately within multiple bodily systems, such as endogenous circadian rhythms in clock-gene expression and synaptic plasticity. These phenomena are well studied; however, it is unknown if and how the 24-h clock affects electrophysiologic network function in vivo. The hippocampus is a region of interest for long timescale (>8 h) studies because it is critical for cognitive function and exhibits time-of-day effects in learning. We recorded single cell spiking activity and local field potentials (LFPs) in mouse hippocampus across the 24-h (12:12-h light/dark) cycle to quantify how electrophysiological network function is modulated across the 24-h day. We found that while inhibitory population firing rates and LFP oscillations exhibit modulation across the day, average excitatory population firing is static. This excitatory stability, despite inhibitory dynamism, may enable consistent around-the-clock function of neural circuits.

Neural activity reflects both external stimuli and the brain\'s internal state, which shapes how information is processed and perceived. An example of modulation of neural responses by network states is phase-precession in the hippocampus, where the phase of theta oscillations affects the firing of single neurons (place cells) and its relation to the external world. Here, we examine a different form of oscillation-to-neuron modulation, where frequency and power of the oscillation, instead of phase, modulate neural firing patterns at the population level. We refer to this as ensemble pattern modulation. To study this effect, we use electrophysiological recordings of rats performing an odour-memory (non-spatial) task. Using a data-driven model, we identified two distinct theta states: low-power-lower-theta (LPLT) and high-power-higher-theta (HPHT). Through decoding analyses, we found that these states differentially modulate hippocampal neural ensemble activity, in this case reflective of the trial outcome. This suggests that amplitude and frequency variations within theta oscillations may reconfigure neural firing at the network level to support distinct cognitive functions.

From an anatomical perspective, the concept that the anterior and posterior hippocampus fulfill distinct cognitive roles may seem unsurprising. When compared with the posterior hippocampus, the anterior region is proportionally larger, with visible expansion of the CA1 subfield and intimate continuity with adjacent medial temporal lobe (MTL) structures such as the uncus and amygdala. However, the functional relevance emerging from these anatomical differences remains to be established in humans. Drawing on both rodent and human data, several models of hippocampal longitudinal specialization have been proposed. For the brevity and clarity of this review, we focus on human electrophysiological evidence supporting and contravening these models with limited inclusion of noninvasive data. We then synthesize these data to propose a novel longitudinal model based on the amount of contextual information, drawing on previous conceptions described within the past decade.

The hippocampus forms unique neural representations for distinct experiences, supporting the formation of different memories. Hippocampal representations gradually change over time as animals repeatedly visit the same familiar environment ("representational drift"). Such drift has also been observed in other brain areas, such as the parietal, visual, auditory, and olfactory cortices. While the underlying mechanisms of representational drift remain unclear, a leading hypothesis suggests that it results from ongoing learning processes. According to this hypothesis, because the brain uses the same neural substrates to support multiple distinct representations, learning of novel stimuli or environments leads to changes in the neuronal representation of a familiar one. If this is true, we would expect drift in a given environment to increase following new experiences in other, unrelated environments (i.e., off-context experiences). To test this hypothesis, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly visited a familiar linear track over weeks. We introduced off-context experiences by placing mice in a novel environment for 1 h after each visit to the familiar track. Contrary to our expectations, these novel episodes decreased place cells' representational drift. Our findings are consistent with a model in which representations of distinct memories occupy different areas within the neuronal activity space, and the drift of each of them within that space is constrained by the area occupied by the others.