Comparison of the timing of hippocampal and subicular spatial signals: implications for path integration

Cells in several portions of the hippocampal formation show location-related firing, so that the momentary rate of each cell signals the spatial location of a freely moving rat. Insight into how these signals are generated, and how they travel around the hippocampal circuitry, can be gained by examination of the exact timing of the locational signal. Here, this was investigated for both hippocampal and subicular cells. For this, several aspects of the spatial firing pattern of each cell were examined over a series of time shifts, in which spikes were paired with locations occupied by the animal in either the immediate past, present, or future. Results showed that subicular cells appear to anticipate future locations by approximately 50 to 70 msec, on average. In contrast, hippocampal cells were best correlated with positions about 30 to 40 msec in the future. However, this timing, for hippocampal cells only, was related to the average session running speed, so that the cells were correlated with future locations at slow speeds, but lagged behind (were correlated with past locations) at high speeds. These data support the idea that both subicular and hippocampal cells use a path integration mechanism to generate their spatial signal (since both can anticipate future location). For the hippocampal cells the mechanism does not, apparently, take into account speed information, however. Also, the data suggest that the subicular signal cannot be the result of simple transmission of spatial information from the hippocampus to the subiculum, since this would predict that the subicular signal should correlate with later positions than the hippocampal signal.     

Competitive Hebbian learning and the hippocampal place cell system: modeling the interaction of visual and path integration cues.

The hippocampus has long been thought essential for implementing a cognitive map of the environment. However, almost 30 years since place cells were found in rodent hippocampal field CA1, it is still unclear how such an allocentric representation arises from an ego-centrically perceived world. By means of a competitive Hebbian learning rule responsible for coding visual and path integration cues, our model is able to explain the diversity of place cell responses observed in a large set of electrophysiological experiments with a single fixed set of parameters. Experiments included changes observed in place fields due to exploration of a new environment, darkness, retrosplenial cortex inactivation, and removal, rotation, and permutation of landmarks. To code for visual cues for each landmark, we defined two perceptual schemas representing landmark bearing and distance information over a linear array of cells. The information conveyed by the perceptual schemas is further processed through a network of adaptive layers which ultimately modulate the resulting activity of our simulated place cells. In path integration terms, our system is able to dynamically remap a bump of activity coding for the displacement of the animal in relation to an environmental anchor. We hypothesize that path integration information is computed in the rodent posterior parietal cortex and conveyed to the hippocampus where, together with visual information, it modulates place cell activity. The resulting network yields a more direct treatment of partial remapping of place fields than other models. In so doing, it makes new predictions regarding the nature of the interaction between visual and path integration cues during new learning and when the system is challenged with environmental changes.     

Lateralized functional components of spatial cognition in the avian hippocampal formation: evidence from single-unit recordings in freely moving homing pigeons

Previous research has revealed that the functional components of spatial cognition are lateralized in the forebrain of birds, including the hippocampal formation (HF). To investigate how HF cells in the left and right avian brain may differentially participate in representations of space, we recorded single-units from the HF of homing pigeons as they ran a plus maze for food. The rate maps of left HF cells often displayed elongated regions of increased activity in the center of the maze and along the maze corridors, whereas right HF cells tended to display patches at the ends of maze arms at/near goal locations. Left HF cells displayed a higher degree of spatial-specificity compared with right HF cells, including higher patch-specificity, higher reliability, and a higher incidence of location-correlated activity. Analysis of speed-correlated and trajectory-dependent activity also revealed significant HF-lateralized differences. Right HF cells tended to display significant negative correlations between spike rate and speed, although speed-dependent rate maps indicate that this relationship did not explain their space-specific activity. Left HF cells displayed a significantly higher incidence of trajectory-dependent space-specific activity than was observed in the right HF, suggesting that left HF cells may participate in navigating among goal locations. Differences in the correlates of left and right pigeon HF cells are consistent with unilateral HF-lesion data suggesting that the functional components of spatial cognition are lateralized in the avian brain, and furthermore, provide a basis for hypotheses regarding how the left and right HF support different aspects of spatial cognition.     

Serial position curves for item (spatial location) information: role of the dorsal hippocampal formation and medial septum

Animals were trained on an item recognition memory task for a list of 5 spatial locations. After reaching criterion performance the animals sustained small or medium-size dorsal hippocampal formation lesions, small or large medial septal lesions, or served as sham-operated or cortical controls. Following recovery from surgery, animals were retested for item recognition memory. Sham-operated and cortical control animals showed no deficits in performance. In contrast, animals with small dorsal hippocampal formation or medial septal lesions displayed a deficit for the early items, but had excellent memory for the last item of the list. Animals with medium-size dorsal hippocampal formation or large medial septal lesions displayed a deficit for both early and late items within the list. Because residual short-term memory capacity can be seen only with small hippocampal formation or medial septal lesions, it is suggested that the hippocampal formation and cholinergic input into the hippocampal formation via the medial septum code spatial information within a continuous extended time frame.     

Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and impairs spatial learning in the guinea pig

Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates γ-aminobutyric acid type A (GABA_A) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA_A receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA_A receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA_A receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the β2/3-subunit of the GABA_A receptor in the hippocampus of young adult offspring. CPEE did not change either [³H]flunitrazepam binding or GABA potentiation of [³H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [³H]flunitrazepam binding, to hippocampal GABA_A receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [³H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA_A receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE.     

Theta band oscillation and synchrony in the hippocampal formation and associated structures: the case for its role in sensorimotor integration.

The current review advances the argument that it is na?ve to ascribe a unitary function to the hippocampal formation (HPC). Rather, it is more productive to consider the hippocampal formation as consisting of a number of subsystems, each subsystem defined by its own particular neural circuitry. Among examples of neural circuitry appearing in current hippocampal literature are theta, beta and gamma oscillations, sharp waves, place cells and head orientation cells. Data are reviewed supporting the case that theta band oscillation and synchrony is involved in mechanisms underlying sensorimotor integration. Specifically, the neural circuitry underlying the production of oscillation and synchrony (theta) in limbic cortex and associated structures function in the capacity of providing voluntary motor systems with continually updated feedback on their performance relative to changing environmental (sensory) conditions. A crucial aspect of this performance is the intensity with which the motor programs are initiated and maintained. The ascending brainstem HPC synchronizing pathways make the primary contribution in this regard. These pathways originate in the rostral pontine region, ascend and synapse with caudal diencephalic nuclei, which in turn send projections to the medial septal region. The medial septum functions as the node in the ascending pathways, sending both cholinergic and GABA-ergic projections to the HPC. An updated version of the sensorimotor integration model including anatomical details is presented and discussed.     

The ups and downs (and lefts and rights) of synaesthetic number forms: Validation from spatial cueing and SNARC-type tasks

Typically, numbers are spatially represented using a mental ‘number line’ running from left to right. Individuals with number-form synaesthesia experience numbers as occupying specific spatial coordinates that are much more complex than a typical number line. Two synaesthetes (L and B) describe experiencing the numbers 1 through 10 running vertically from bottom to top, 10-20 horizontally from left to right, 21-40 from right to left, etc. We investigated whether their number forms could bias their spatial attention using a cueing paradigm and a SNARC-type task. In both experiments, the synaesthetes' responses confirmed their synaesthetic number forms. When making odd-even judgments for the numbers 1, 2, 8, and 9, they showed SNARC-compatibility effects for up-down movements (aligned with their number form), but not left-right (misaligned) movements. We conceptually replicated these biases using a spatial cueing paradigm. Both synaesthetes showed significantly faster response times to detect targets on the bottom of the display if preceded by a low number (1, 2), and the top of the display if preceded by a high number (8, 9), whereas they showed no cueing effects when targets appeared on the left or right (misaligned with their number forms). They were however reliably faster to detect left targets following the presentation of numbers 10 and 11, and right targets following numbers 19 and 20 (since 10-20 runs from left to right). In sum, cueing and SNARC tasks can be used to empirically verify synaesthetic number forms, and show that numbers can direct spatial attention to these idiosyncratic locations.     

Light modulates hippocampal function and spatial learning in a diurnal rodent species: A study using male nile grass rat (Arvicanthis niloticus)

The effects of light on cognitive function have been well‐documented in human studies, with brighter illumination improving cognitive performance in school children, healthy adults, and patients in early stages of dementia. However, the underlying neural mechanisms are not well understood. The present study examined how ambient light affects hippocampal function using the diurnal Nile grass rats (Arvicanthis niloticus) as the animal model. Grass rats were housed in either a 12:12 h bright light–dark (brLD, 1,000 lux) or dim light‐dark (dimLD, 50 lux) cycle. After 4 weeks, the dimLD group showed impaired spatial memory in the Morris Water Maze (MWM) task. The impairment in their MWM performance were reversed when the dimLD group were transferred to the brLD condition for another 4 weeks. The results suggest that lighting conditions influence cognitive function of grass rats in a way similar to that observed in humans, such that bright light is beneficial over dim light for cognitive performance. In addition to the behavioral changes, grass rats in the dimLD condition exhibited reduced expression of brain‐derived neurotrophic factor (BDNF) in the hippocampus, most notably in the CA1 subregion. There was also a reduction in dendritic spine density in CA1 apical dendrites in dimLD as compared to the brLD group, and the reduction was mostly in the number of mushroom and stubby spines. When dimLD animals were transferred to the brLD condition for 4 weeks, the hippocampal BDNF and dendritic spine density significantly increased. The results illustrate that not only does light intensity affect cognitive performance, but that it also impacts hippocampal structural plasticity. These studies serve as a starting point to further understand how ambient light modulates neuronal and cognitive functions in diurnal species. A mechanistic understanding of the effects of light on cognition can help to identify risk factors for cognitive decline and contribute to the development of more effective prevention and treatment of cognitive impairment in clinical populations.     

The conjoint importance of the hippocampus and anterior thalamic nuclei for allocentric spatial learning: evidence from a disconnection study in the rat

A disconnection procedure was used to test whether the hippocampus and anterior thalamic nuclei form functional components of the same spatial memory system. Unilateral excitotoxic lesions were placed in the anterior thalamic (AT) nuclei and hippocampus (HPC) in either the same (AT-HPC Ipsi group) or contralateral (AT-HPC Contra group) hemispheres of rats. The behavioral effects of these combined lesions were compared in several spatial memory tasks sensitive to bilateral hippocampal lesions. In all of the tasks tested, T-maze alternation, radial arm maze, and Morris water maze, those animals with lesions placed in the contralateral hemispheres were more impaired than those animals with lesions in the same hemisphere. These results provide direct support for the notion that the performance of tasks that require spatial memory rely on the operation of the anterior thalamus and hippocampus within an integrated neural network.     

Internal connectivity of the homing pigeon (Columba livia) hippocampal formation: an anterograde and retrograde tracer study

The avian hippocampal formation (HF) is a structure necessary for learning and remembering aspects of environmental space. Therefore, understanding the connections between different HF regions is important for determining how spatial learning processes are organized within the avian brain. The prevailing feed-forward, trisynaptic internal connectivity of the mammalian hippocampus and its importance for cognition have been well described, but the internal connectivity of the avian HF has only recently been investigated. To examine further the connectivity within the avian HF, small amounts of cholera toxin subunit B, primarily a retrograde tracer (n = 15), or biotinylated dextran amine, primarily an anterograde tracer (n = 10), were injected into localized regions of the HF. Examination of the immunohistochemically labeled tissue showed projections from extrinsic sensory processing areas into dorsolateral HF and the dorsal portion of the dorsomedial HF (DMd). DMd in turn projected into the medial (VM) and lateral (VL) ventral cell layers. A projection from VM into VL was found, and together these areas and DM provided input into the contralateral ventral cell layers. Ipsilaterally, a ventral portion of dorsomedial HF (DMv) received input from VL and VM. From DMv, projections exited HF laterally. The highlighted projections formed a discernible feed-forward processing network through the avian HF that resembled the trisynaptic circuit of the mammalian HF.     

Mice lacking leukocyte common antigen-related (LAR) protein tyrosine phosphatase domains demonstrate spatial learning impairment in the two-trial water maze and hyperactivity in multiple behavioural tests

Leukocyte common antigen-related (LAR) protein is a cell adhesion molecule-like receptor-type protein tyrosine phosphatase. We previously reported that in LAR tyrosine phosphatase-deficient (LAR-Delta P) mice the number and size of basal forebrain cholinergic neurons as well as their innervation of the hippocampal area was reduced. With the hippocampus being implicated in behavioural activity aspects, including learning and memory processes, we assessed possible phenotypic consequences of LAR phosphatase deficiency using a battery of rodent behaviour tests. Motor function and co-ordination tests as well as spatial learning ability assays did not reveal any performance differences between wildtype and LAR-Delta P mice. A spatial learning impairment was found in the difficult variant of the Morris water maze. Exploration, nestbuilding and activity tests indicated that LAR-Delta P mice were more active than wildtype littermates. The observed hyperactivity in LAR-Delta P mice could not be explained by altered anxiety or curiosity levels, and was found to be persistent throughout the nocturnal period. In conclusion, behavioural testing of the LAR-Delta P mice revealed a spatial learning impairment and a significant increase in activity.     

Effect of thyroid deficiency on glial fibrillary acidic protein (GFAP) and GFAP-mRNA in the cerebellum and hippocampal formation of the developing rat.

The concentrations of glial fibrillary acidic protein (GFAP) and its encoding mRNA in the cerebellum and hippocampal formation were assayed during the development of normal and hypothyroid rats. Neonatal hypothyroidism induced a significant reduction in the GFAP concentration in both regions from day 14. The reduction was especially marked on day 35 in the cerebellum (-43%) and the hippocampal formation (-55%). The immunocytochemical study of vimentin showed that the developmental disappearance of this protein from the Bergmann and internal astrocytes is greatly delayed in the cerebellum of the hypothyroid rats. The reduction in GFAP concentration together with the delayed vimentin-GFAP transition could explain how astrocyte morphogenesis is impaired by neonatal thyroid deficiency. The GFAP-mRNA concentration in the hippocampal formation was reduced throughout the development of thyroid-deficient rats, while the GFAP-mRNA concentration in the cerebellum first increased between birth and day 14 to reach a peak well above the normal value (+78%) and decreased thereafter to reach 53% of the normal value by day 35. This transient increase in the cerebellar GFAP-mRNA concentration may be related to the astroglial hyperplasia that occurs in these animals. The difference between the developmental profile of GFAP and its encoding mRNA, especially under pathological conditions, indicates that two distinct mechanisms control the synthesis or stability of the protein and its messenger RNA, as was previously found in the forebrain of the developing normal rat.     

Extrinsic projections from area CA1 of the rat hippocampus: olfactory, cortical, subcortical, and bilateral hippocampal formation projections.

Hippocampal area CA1 provides the major cortical output of the hippocampus, but only its projections to the subiculum and lateral septal nucleus are well characterized. The present study reexamines these extrinsic projections by using anterograde and retrograde tracing techniques. Injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) in the septal one-third of CA1 label axons and terminals in subicular, postsubicular, retrosplenial, perirhinal, and entorhinal cortices, lateral septal nucleus, and diagonal band of Broca. The septal CA1 injections also label terminal fields in contralateral CA1, and in contralateral subicular, postsubicular, perirhinal, and entorhinal cortices. Injections into the splenial one-third of CA1 label axons and terminals in subiculum, postsubiculum, ventral area infraradiata, and lateral septal nucleus, but they do not label axons and terminals on the contralateral side of the brain. Injections in the temporal one-third of CA1 label axons and terminals in subicular, parasubicular, entorhinal, and infraradiata cortices, anterior olfactory nucleus, olfactory bulb, lateral septal nucleus, nucleus accumbens, amygdala, and hypothalamus. The temporal CA1 injections label no axons on the contralateral side of the brain. These data demonstrate that CA1 has more widespread projections than previously appreciated, and they provide the first clear evidence that CA1 projects to the contralateral cortex and to the ipsilateral olfactory bulb, amygdala, and hypothalamus. The results also demonstrate a heterogeneity in the efferent projections originating in different septotemporal levels of CA1.     

Implicit learning and reading: Insights from typical children and children with developmental dyslexia using the artificial grammar learning (AGL) paradigm

We examined implicit learning in school-aged children with and without developmental dyslexia based on the proposal that implicit learning plays a significant role in mastering fluent reading. We ran two experiments with 16 typically developing children (9 to 11-years-old) and 16 age-matched children with developmental dyslexia using the artificial grammar learning (AGL) paradigm. In Experiment 1 (non-transfer task), children were trained on stimuli that followed patterns (rules) unknown to them. Subsequently, they were asked to decide from a novel set which stimuli follow the same rules (grammaticality judgments). In Experiment 2 (transfer task), training and testing stimuli differed in their superficial characteristics but followed the same rules. Again, children were asked to make grammaticality judgments. Our findings expand upon previous research by showing that children with developmental dyslexia show difficulties in implicit learning that are most likely specific to higher-order rule-like learning. These findings are discussed in relation to current theories of developmental dyslexia and of implicit learning.     

Distribution of neurotransmitter receptors and zinc in the pigeon (Columba livia) hippocampal formation: A basis for further comparison with the mammalian hippocampus

The avian hippocampal formation (HF) and mammalian hippocampus share a similar functional role in spatial cognition, but the underlying neuronal mechanisms allowing the functional similarity are incompletely understood. To understand better the organization of the avian HF and its transmitter receptors, we analyzed binding site densities for glutamatergic AMPA, NMDA, and kainate receptors; GABA_A receptors; muscarinic M₁, M₂ and nicotinic (nACh) acetylcholine receptors; noradrenergic α₁ and α₂ receptors; serotonergic 5‐HT_1A receptors; dopaminergic D_1/5 receptors by using quantitative in vitro receptor autoradiography. Additionally, we performed a modified Timm staining procedure to label zinc. The regionally different receptor densities mapped well onto seven HF subdivisions previously described. Several differences in receptor expression highlighted distinct HF subdivisions. Notable examples include 1) high GABA_A and α₁ receptor expression, which rendered distinctive ventral subdivisions; 2) high α₂ receptor expression, which rendered distinctive a dorsomedial subdivision; 3) distinct kainate, α₂, and muscarinic receptor densities that rendered distinctive the two dorsolateral subdivisions; and 4) a dorsomedial region characterized by high kainate receptor density. We further observed similarities in receptor binding densities between subdivisions of the avian and mammalian HF. Despite the similarities, we propose that 300 hundred million years of independent evolution has led to a mosaic of similarities and differences in the organization of the avian HF and mammalian hippocampus and that thinking about the avian HF in terms of the strict organization of the mammalian hippocampus is likely insufficient to understand the HF of birds. J. Comp. Neurol. 522:2553–2575, 2014. © 2014 Wiley Periodicals, Inc.     

Corticotropin-releasing hormone (CRH)-containing neurons in the immature rat hippocampal formation: Light and electron microscopic features and colocalization with glutamate decarboxylase and parvalbumin

Corticotropin-releasing hormone (CRH) excites hippocampal neurons and induces death of selected CA3 pyramidal cells in immature rats. These actions of CRH require activation of specific receptors that are abundant in CA3 during early postnatal development. Given the dramatic effects of CRH on hippocampal neurons and the absence of CRH-containing afferents to this region, we hypothesized that a significant population of CRHergic neurons exists in developing rat hippocampus. This study defined and characterized hippocampal CRH-containing cells by using immunocytochemistry, ultrastructural examination, and colocalization with gamma-aminobutyric acid (GABA)-synthesizing enzyme and calcium-binding proteins. Numerous, large CRH-immunoreactive (ir) neurons were demonstrated in CA3 strata pyramidale and oriens, fewer were observed in the corresponding layers of CA1, and smaller CRH-ir cells were found in stratum lacunosum-moleculare of Ammon's horn. In the dentate gyrus, CRH-ir somata resided in the granule cell layer and hilus. Ultrastructurally, CRH-ir neurons had aspiny dendrites and were postsynaptic to both asymmetric and symmetric synapses. CRH-ir axon terminals formed axosomatic and axodendritic symmetric synapses with pyramidal and granule cells. Other CRH-ir terminals synapsed on axon initial segments of principal neurons. Most CRH-ir neurons were coimmunolabeled for glutamate decarboxylase (GAD)-65 and GAD-67 and the majority also contained parvalbumin, but none were labeled for calbindin. These results confirm the identity of hippocampal CRH-ir cells as GABAergic interneurons. Further, a subpopulation of neurons immunoreactive for both CRH and parvalbumin and located within and adjacent to the principal cell layers consists of basket and chandelier cells. Thus, axon terminals of CRH-ir interneurons are strategically positioned to influence the excitability of the principal hippocampal neurons via release of both CRH and GABA. Hippocampus 1998;8: 231–243. © 1998 Wiley-Liss, Inc.     

Antiepileptic drugs and the regulation of mood and quality of life (QOL): the evidence from epilepsy

We review the literature on the influence of antiepileptic drugs (AEDs) on mood and quality of life in patients with epilepsy. Although many anecdotal reports cover a spectrum of AEDs, most of the controlled data have come from studies of carbamazepine and lamotrigine. Both of these compounds appear to have positive effects on mood, and these data parallel the effects noted in nonepilepsy populations. AEDs that are gamma-aminobutyric acid (GABA)ergic tend to have negative effects on mood, and an affective disorder is often noted as a treatment-emergent effect. It is speculated that the amygdala is an important anatomic structure in the cerebral circuits that regulate mood in affective disorders but also in epilepsy, and an effect of AEDs on such circuits aids mood stability in both populations of patients.