Hippocampus (Brain)

Considerable research has been carried out to establish a rodent model for the
study of human memory, yet functional similarities between the species remain up for
debate. The hippocampus, a region deep within the medial temporal lobe of the
mammalian CNS, is critical for long-term episodic memory. Projections from the medial
entorhinal cortex convey spatial/contextual information, while projections from the
lateral entorhinal cortex convey item/object information to the hippocampus. The
functional significance of these parallel projections to the rodent hippocampus has been
suggested to support spatial processing, while the same projections to the human
hippocampus support spatial and non-spatial memory. Discharging in a location-specific
manner, hippocampal place cells contribute to spatial memory; however, evidence for
neuronal correlates of non-spatial object memory has not been fully defined. The current
experiments were designed to address the following questions, while utilizing
electrophysiology, functional inactivation during a novel behavioral task, and immunohistochemistry. Is the memory for objects hippocampal-dependent, solely due to
the location of the object, or are objects represented within hippocampal activity
independent of location? To tease apart spatial and non-spatial processing by the
hippocampus, the spatial aspects of 3D objects were enhanced by utilizing movement. A
novel discriminatory avoidance task, Knowing Your Enemy, was adapted from an Enemy
Avoidance task to test true object memory in mice. Current findings support the notion
that object-associations acquisition depends upon a specific context. Retrieval of such
object-associations is not context-dependent, yet remains sensitive to temporary
inactivation of the CA1 region of the dorsal hippocampus. The avoidance impairments
observed following hippocampal inactivation were shown to not be a result of reduced
anxiety. Immunohistochemical marker expression suggests that the CA1 region was
highly active during object exposures, yet the hippocampal system responded
differentially to moving and to stationary objects. Recordings of CA1 neurons yielded
non-bursting object-related activity during object exploration, and place cell activity
remained unaffected in the presence of moving objects; supporting independent, yet
simultaneous processing of spatial and non-spatial information within the hippocampus.
Together, the current findings support the notion that the CA1 region of the rodent
hippocampus processes object-related information, independent of spatial information.

SK channels are small conductance Ca2+-activated K+ channels expressed throughout the CNS. SK channels modulate the excitability of hippocampal CA1 neurons by affecting afterhyperpolarization and shaping excitatory postsynaptic responses. Such SK-mediated effects on activity-dependent neuronal excitability and synaptic strength are thought to underlie the modulatory influence of SK channels on memory encoding. Here,the effect of a new SK1 selective activator, GW542573X, on hippocampal-dependent object memory, contextual and cued conditioning, and trace fear conditioning was examined. The results demonstrated that pre- but not post-training systemic administration of GW542573X impaired object memory and trace fear memory in mice 24 h after training. Contextual and cued fear memory were not disrupted. These current data suggest that activation of SK1 subtype-containing SK channels impairs long-term memory. These results are consistent with converging evidence that SK channel activation suppressed behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory.

Projections of the nucleus reticularis pontis oralis (RPO), the pedunculopontine tegmental nucleus (PPT) and the median raphe nucleus (MR) were examined using the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). The RPO projected strongly throughout the reticular core, to the PPT and to the intralaminar thalamic nuclei. Light projections were observed in the posterior hypothalamus but not the supramammillary nucleus. The pattern of labeling suggests that the RPO is arranged topographically in longitudinal columns. The PPT projected to the RPO, MR, medial thalamic and intralaminar nuclei, the supramammillary nucleus and septum. The MR was found to project heavily to the supramammillary nucleus, intralaminar thalamic nuclei, the septum, the hippocampus and several cortical areas. The results are discussed in terms of the modulation of hippocampal EEG and a model is introduced emphasizing interactions among ascending hippocampal EEG synchronizing and desynchronizing systems.

Recent evidence suggests that the supramammillary nucleus (SUM) is an important link from the pontine reticular formation (PRF) to the septum-hippocampus in the generation of hippocampal theta rhythm. I proposed: (1) injections of WGA-HRP into the SUM would produce retrograde labeling in PRF cells; (2) lesions of the SUM would produce a reduction in the frequency and amplitude of hippocampal theta rhythm; (3) injections of procaine into the SUM would attenuate the amplitude and reduce the frequency of reticular elicited theta rhythm. Although WGA-HRP injections in the SUM produced minimal labeling in the PRF, there were labeled cells in the central gray of the pons, and in the dorsal raphe and surrounding regions. I found that lesions of the SUM produced minimal changes in the frequency and amplitude of theta in the behaving animal but that injections of procaine attenuated both of these measures in the urethane anesthetized rat.

Performance on three preoperative and three postoperative
copulation tests was compared for male rats given dorsal
hippocampal, dorsal hippocampal plus cortical, other lesion,
and sham lesions. Dorsal hippocampal lesions produced
statistically significant changes in the temporal pacing
of some components of sexual behavior, i.e. the post-ejaculatory interval, intercopulatory interval, and total
test time decreased. Hippocampal plus cortical lesions
had no effect on sexual behavior. The results are interpreted
as supporting a model of inhibition in which a
sexual inhibitory process is built up concomitantly with
the sexual arousal process.

Rats with bilateral, electrolytic, dorsal-hippocampal lesions
were compared with operated controls in a straight runway to assess
the effects of the lesion on the animals' reactions to food-incentive
shifts. Within each surgical group, half the animals received 40
preshift trials with low reward while the other half received the same
number of trials with high reward, following this all Ss were shifted
to the opposite reward magnitude and received 40 additional trials.
At this point, the Ss were shifted back to original reward magnitudes
for another 40 trials. Finally, all Ss underwent experimental
extinction. The data failed to support the hypothesis that dorsal
hippocampal rats "overreact" to incentive shifts. Lesion animals, as
compared to controls, were less sensitive to the reward shifts and
showed more resistance to extinction. The results suggest that the
lesion produces a deficit in the Ss ability to vary behavior specially
on tasks that require response decrements. However, the lesion-produced
hyperactivity introduced confounding aspects to this interpretation.

Coherence estimates have been used to determine the presence of functional coupling between two signals. While direct projections from the nucleus reuniens (RE) to the hippocampus formation in the rat have been discovered, little is known about the possible functional influence of the RE on the hippocampus. This investigation makes use of MATLAB to create a set of specialized algorithms to investigate coherence function estimates between RE cell activity and hippocampal EEG. In addition, error prevention considerations as well as shortcomings in current data acquisition software that ultimately lead to the necessity for additional software analysis tools are also discussed. An investigation into RE cell behavior requires the calculation of cell activity spike rates as well as the identification of action potential bursting phenomena. Isolation of individual cell activity, from a population recording channel, is needed in order to prevent erroneous effects associated with using unresolved multi-neuron recordings. Changes in spike rate activity and frequency of bursting occurrences are calculated as a means of gauging RE unit response to the presence of a stimulus (e.g., tail pinch). The relationship of RE units on hippocampal EEG by analysis of coherence function estimates between RE units and hippocampal EEG, as well as evaluated RE unit behavior in terms of changes in unit spike rate and bursting activity are established.

Single unit activity from the anterior thalamus (AT) was recorded in order to investigate discharge profiles during desynchronized (large amplitude irregular activity (LIA)), and synchronized (theta rhythm) patterns of the hippocampal EEG. Units were recorded in urethane-anesthetized rats in the anteroventral (AV, n = 96), the anterodorsal (AD, n = 44) and the anteromedial (AM, n = 48) thalamic nuclei. The majority of the units (n = 164, 87%) were theta-on and a small group (n = 24, 13%) was theta-off. Theta-off cells were found in AD and AM nuclei but not in AV. Theta-on cells increased their discharge in presence of hippocampal theta. Mean discharge rate was 6.0 +/- 0.52 Hz and 14.48 +/- 0.96 Hz for AV theta-on cells during control and theta states, 4.43 +/- 0.52 Hz and 10.05 +/- 1.28 Hz for AD theta-on cells, and 2.60 +/- 0.3 Hz and 6.42 +/- 0.9 Hz for AM theta-on cells, respectively. We found that 40% of AV cells showed a rhythmic pattern that peaked significantly at 250--270 ms during theta, 21.9% of AD units and only 5.7% for AM units showed a rhythmic pattern. The majority of AT cells showed unit-theta phase-locked EEG oscillations in the crosscorrelogram, indicating that in spite of low rhythmicity most units firing were modulated at theta frequency. The coherence measured by spectral analysis between unit firing and hippocampal theta was statistically significant in 75% of cases. The anatomical distribution of the cells shows that coherence values were widely distributed across the anterior thalamus. In addition, the particular contribution of this diencephalic structure during theta was determined by applying measures of information flow in the neural circuit of Papez. Partial coherence (PC) analysis together with the computation of causality measures (DTF and DC) was used to study such interaction among AV, retrosplenial cortex and hippocampus. PC analysis revealed hippocampus as the synchronizing structure for rhythmic AV cells and retrosplenial cortex. A link between hippocampus and retrosplenial cortex was found for the non-rhythmic AV group. The DTF analysis showed flow of propagation from AV to hippocampus, hippocampus to retrosplenial cortex and AV to retrosplenial cortex for both groups. The strength of connection changed depending on the state of the animal. Behaviors that have been particularly related to the hippocampal theta activity refer mainly to learning and memory. Activation of large numbers of septo-hippocampal neurons during the generation of the theta rhythm has been proposed as a 'natural tetanizer'. Numerous cellular studies have linked long-term potentiation (LTP) and the hippocampal theta rhythm. The role of theta in memory has been evidenced through lesion studies in animals. Some observations in humans have proposed the anterior thalamus as pivotal for spatial memory. Perhaps the cellular theta activity found in AV plays an important role in the generation and control of the hippocampal theta rhythm and hence in memory and learning.

The rodent hippocampus is critical for processing spatial memory but its contribution to non-spatial, specifically object memory is debated. The cognitive map theory of hippocampal function states that the hippocampus stores relationships of goal locations (places) to discrete items (objects) encountered within environments. Dorsal CA1 place cells were recorded in male C57BL/6J mice performing three variations of the novel object recognition paradigm to define "object-in-context" representation of hippocampal neuronal activity that may support object memory. Results indicate, (i) that place field stability is higher when polarizing environmental cues are provided during object recognition; (ii) hippocampal place fields remain stable throughout the novel object recognition testing without a polarizing cue; and (iii) time dependent effects on stability when objects were dissociated from the context. These data indirectly support that the rodent hippocampus processes object memory, and challenge the view that "object-in-context" representations are formed when mice perform novel object recognition task.