Sean Commins

Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus

We investigated the effects of a single injection and a daily injection of lipopolysaccharide (LPS) on spatial learning and brain-derived neurotrophic factor (BDNF) expression in the rat dentate gyrus. LPS is derived from the cell wall of Gram-negative bacteria and is a potent endotoxin that causes the release of cytokines such as interleukin-1 and tumour necrosis factor. LPS is thought to activate both the neuroimmune and neuroendocrine systems; it also blocks long-term potentiation in the hippocampus. Here, we examined the effects of LPS on a form of hippocampal-dependent learning-spatial learning in the water maze. Rats were injected with LPS intraperitoneally (100 microg/kg) and trained in the water maze. The first group of rats were injected on day 1 of training, 4 h prior to learning the water maze task. Groups 2 and 3 were injected daily, again 4 h prior to the water-maze task; group 2 with LPS and group 3 with saline. A number of behavioural variables were recorded by a computerised tracking system for each trial. The behavioural results showed a single injection of LPS (group 1) impaired escape latency in both the acquisition and retention phases of the study, whereas a daily injection of LPS did not significantly impair acquisition or retention. BDNF expression was analysed in the dentate gyrus of all animals. No significant differences in BDNF expression were found between the three groups.

Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad-spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain-derived neurotrophic factor.

Cyclooxygenase (COX), which is present in two isoforms (COX1 and 2), synthesizes prostaglandins from arachidonic acid; it plays a crucial role in inflammation in both central and peripheral tissues. Here, we describe its role in synaptic plasticity and spatial learning in vivo via an effect on brain‐derived neurotrophic factor (BDNF) and prostaglandin E2 (PGE2; both measured by Elisa). We found that broad‐spectrum COX inhibition (BSCI) inhibits the induction of long‐term potentiation (LTP; the major contemporary model of synaptic plasticity), and causes substantial and sustained deficits in spatial learning in the watermaze. Increases in BDNF and PGE2 following spatial learning and LTP were also blocked. Importantly, 4 days of prior exercise in a running wheel increased endogenous BDNF levels sufficiently to reverse the BSCI of LTP and spatial learning, and restored a parallel increase in LTP and learning‐related BDNF and PGE2. In control experiments, we found that BSCI had no effect on baseline synaptic transmission or on the nonhippocampal visible‐platform task; there was no evidence of gastric ulceration from BSCI. COX2 is inhibited by glucorticoids; there was no difference in blood corticosterone levels as measured by radioimmunoassay in any condition. Thus, COX plays a previously undescribed, permissive role in synaptic plasticity and spatial learning via a BDNF‐associated mechanism.

Massed but not spaced training impairs spatial memory

The Morris water maze and the object displacement task are two popular tools used to investigate spatial learning and memory. Research has focused mainly on the acquisition of spatial tasks while little attention has been given to the retention phase. We examined the effects of different training procedures on retention of the water maze and also reactivity to spatial change in the object displacement task 7 days post-acquisition. We found that massed-trained animals were impaired on retention of the water maze compared to those animals that had received spaced-training. We also found that the massed-trained animals habituated readily to their environment in the object displacement task while the spaced-trained group did not. Furthermore the massed-trained group did not react to spatial change 7 days post-habituation compared to the increased reactivity displayed by the spaced-trained group. Results are discussed in terms of poor encoding of the environment leading to poor retention.

The rat perirhinal cortex: A review of anatomy, physiology, plasticity, and function

The perirhinal cortex is located in a pivotal position to influence the flow of information into and out of the hippocampal formation. In this review, we examine the anatomical, physiological and functional properties of the rat perirhinal cortex. Firstly, we review the properties of the perirhinal cortex itself, we describe how it can be separated into two distinct subregions and consider how it differs from other neighbouring regions in terms of cell type, cellular organisation and its afferent and efferent projections. We review the forms of neurotransmission present in the perirhinal cortex and the morphological, electrophysiological and plastic properties of its neurons. Secondly, we review the perirhinal cortex in the context of its connections with other brain areas; focussing on the projections to cortical, subcortical and hippocampal/parahippocampal regions. Particular attention is paid the anatomical and electrophysiological properties of these projections. Thirdly, we review the main functions of the perirhinal cortex; its roles in perception, recognition memory, spatial and contextual memory and fear conditioning are explored. Finally, we discuss the idea of anatomical, electrophysiological and functional segregation within the perirhinal cortex itself and as part of a hippocampal-parahippocampal network and suggest that understanding this segregation is of critical importance in understanding the role and contributions made by the perirhinal cortex in general.

Interaction between paired-pulse facilitation and long-term potentiation in the projection from hippocampal area CA1 to the subiculum.

Studies of the interaction between long-term potentiation (LTP) and paired-pulse facilitation (PPF) may throw light on the role of presynaptic factors in LTP. We examine here, for the first time, the nature of PPF in the CA1-subiculum projection. PPF peaks at a 50 ms interstimulus interval (ISI) and is evident at ISIs from 10 to 500 ms. There is no PPF effect at a 1000 ms ISI. PPF decreases in magnitude post-LTP induction across the middle range of ISI values tested (30, 50 and 100 ms). There is a positive correlation between initial PPF values and LTP; this correlation increases as the ISI increases. Initial values and the change in PPF post-LTP are also negatively correlated.

Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse

Post-septic encephalopathy is a poorly understood condition in survivors of sepsis that is characterised by cognitive and affective impairments. In this study we have sought to better understand this condition by undertaking a comprehensive behavioural and cognitive assessment of mice who had previously survived sepsis. Mice were treated with lipopolysaccharide (LPS; 5mg/kg) and one month after this assessed on a battery of tests. Post-septic animals were found to display significantly more immobility in the tail suspension test and show a significantly decreased sucrose preference. Acute fluoxetine treatment reversed the increase in immobility in the tail suspension test in post-septic animals. Post-septic animals also showed less overall exploratory behaviour in the novel object recognition task and also showed increased anxiety-like behaviour in the elevated plus maze. Post-septic mice did not show signs of cognitive impairment, as assessed in the Morris watermaze, the 8-arm radial maze or on preference for the novel object in the novel object recognition task. Immunohistochemical analysis revealed significant upregulation of the microglial marker CD-11b, F4/80 and IBA-1 in the hippocampus of post-septic animals, as well as significant downregulation of the plasticity-related immediate early gene products ARC and EGR1. We also observed a decrease in neural stem cell proliferation in the dentate gyrus of post-septic animals as judged by BrdU incorporation. Co-treatment with the NF-κB pathway inhibitor PDTC attenuated the long-lasting effects of LPS on most of the affected parameters, but not on neural stem cell proliferation. These results show that LPS-induced sepsis in the mouse is followed by long-lasting increases in depressive- and anxiety-like behaviours, as well as by changes in neuroinflammatory- and neural plasticity-associated factors, and that attenuation of the severity of sepsis by PDTC attenuates many of these effects.

The projection from hippocampal area CA1 to the subiculum sustains long- term potentiation

LONG-TERM potentiation (LTP) is a popular model of the synaptic plasticity which may be engaged by the biological processes underlying learning and memory. Most available studies of LTP have concentrated on the analysis of LTP occurring in ‘early’ components of the hippocampal circuit (for example, dentate gyrus and area CA1). We examine here, for the first time, LTP as it occurs in the massive, unidirectional projection from CA1 to the subiculum in vivo. We show that this projection sustains high-frequency stimulus-induced LTP (10 trains of 20 stimuli at 20 0 Hz; intertrain interval 2 s; LTP 181 ± 9% at 30 min post-LTP induction). In addition, input-output (I/O) curves show a leftward shift for all stimulation values.

Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal‐cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long‐term potentiation (LTP) and paired‐pulse facilitation (PPF, a short‐term plastic effect). Although we failed to induce long‐term depression (LTD) of this pathway with low‐frequency stimulation (LFS) and two‐pulse stimulation (TPS), both protocols can induce a “late‐developing” potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired‐pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired‐pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short‐term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely‐moving animal, and provide a description of the characteristics of such neurons in a pellet‐chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory. Hippocampus 10:447–456, 2000

Physiological evidence for a possible projection from dorsal subiculum to hippocampal area CA1

The substantial forward projection from hippocampal area CA1 to the subiculum has been comprehensively described, both anatomically and neurophysiologically. There are few data, however, regarding the existence of a backward projection from the subiculum to area CA1. We present here new electrophysiological evidence for the existence of this projection. We demonstrate a positive-going deflection in the evoked synaptic response in area CA1 following stimulation in dorsal subiculum. We also found a small, but significant, paired-pulse facilitatory effect at a 100-ms interstimulus interval. We were unable to induce long-term potentiation following high-frequency stimulation, but were able to induce short-term potentiation.

Cyclooxygenase inhibition attenuates endotoxin-induced spatial learning deficits, but not an endotoxin-induced blockade of long-term potentiation.

Peripheral administration of lipopolysaccharide (LPS), a potent bacterial endotoxin, can cause a variety of central effects, including production of cytokines and cyclooxygenases in the brain, as well as peripheral increases in corticosterone. These, in turn, may contribute to neuroimmune-induced neurocognitive deficits. We show here LPS causes deficits in hippocampal-dependent spatial learning in the water maze but that treatment with ibuprofen, a broad-spectrum cyclooxygenase inhibitor, reverses the deficits induced in spatial learning by LPS. We also show that LPS causes an impairment in the induction of long-term potentiation in the dentate gyrus in vivo, a major contemporary model of learning and memory. No differences were found in corticosterone levels in trunk blood but we find a decrease in brain-derived neurotrophic factor (BDNF) expression in LPS group compared to saline controls. Paradoxically compared to the behavioral findings treatment with ibuprofen does not attenuate the LPS-induced impairment in LTP or BDNF concentration in tetanized tissue.