Intracerebral Transplants and Memory Dysfunction: Circuitry Repair or Functional Level Setting?

Intracerebral grafting techniques of fetal neural cells have been used essentially with two main types of lesion paradigms, namely damage to long projection systems, in which the source and the target are clearly separate, and damage to neurons that are involved in local circuits within a small (sub)region of the brain. With the’first lesion paradigm, grafts placed homotopically (in the source) are not appropriate because their fibers grow poorly through the host parenchyma and fail to reach their normal target. To be successful, the grafts must be placed ectopically in the target region of the damaged projection systems, where generally they work as level-setting systems. Conversely, with the second paradigm, the grafts are supposed to compensate for a local loss of neurons and must be placed homotopically to induce functional effects that are based on the reconstruction of a point-to-point circuitry. By inserting a biological or artificial bridging-substrate between the source and the target of long projection systems, it might be possible to combine the positive effects of both homotopic and ectopic grafting by achieving both target reinnervation and normal control of the grafted neurons within the source area. These issues are illustrated and discussed in this review

Modulation of cholinergic functions by serotonin and possible implications in memory: General data and focus on 5-HT1A receptors of the medial septum

Cholinergic systems were linked to cognitive processes like attention and memory. Other neurotransmitter systems having minor influence on cognitive functions - as shown by the weakness of the effects of their selective lesions - modulate cholinergic functions. The serotonergic system is such a system. Conjoined functional changes in cholinergic and serotonergic systems may have marked cognitive consequences [Cassel JC, Jeltsch H. Serotoninergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69(1):1-41; Steckler T, Sahgal A. The role of serotoninergic-cholinergic interactions in the mediation of cognitive behaviour. Behav Brain Res 1995;67:165-99]. A crucial issue in that concern is the identification of the neuroanatomical and neuropharmacological substrates where functional effects of serotonergic/cholinergic interactions originate. Approaches relying on lesions and intracerebral cell grafting, on systemic drug-cocktail injections, or even on intracerebral drug infusions represent the main avenues on which our knowledge about the role of serotonergic/cholinergic interactions has progressed. The present review will visit some of these avenues and discuss their contribution to what is currently known on the potential or established implication(s) into memory functions of serotonergic/cholinergic interactions. It will then focus on a brain region and a neuropharmacological substrate that have been poorly studied as regards serotonergic modulation of memory functions, namely the medial septum and its 5-HT(1A) receptors. Based on recent findings of our laboratory, we suggest that these receptors, located on both cholinergic and GABAergic septal neurons, take part in a mechanism that controls encoding, to some extent consolidation, but not retrieval, of hippocampal-dependent memories. This control, however, does not occur by the way of an exclusive action of serotonin on cholinergic neurons

A Wireless EEG Recording Method for Rat Use inside the Water Maze

With the continued miniaturisation of portable embedded systems, wireless EEG recording techniques are becoming increasingly prevalent in animal behavioural research. However, in spite of their versatility and portability, they have seldom been used inside water-maze tasks designed for rats. As such, a novel 3D printed implant and waterproof connector is presented, which can facilitate wireless water-maze EEG recordings in freely-moving rats, using a commercial wireless recording system (W32; Multichannel Systems). As well as waterproofing the wireless system, battery, and electrode connector, the implant serves to reduce movement-related artefacts by redistributing movement-related forces away from the electrode connector. This implant/connector was able to successfully record high-quality LFP in the hippocampo-striatal brain regions of rats as they undertook a procedural-learning variant of the double-H water-maze task. Notably, there were no significant performance deficits through its use when compared with a control group across a number of metrics including number of errors and speed of task completion. Taken together, this method can expand the range of measurements that are currently possible in this diverse area of behavioural neuroscience, whilst paving the way for integration with more complex behaviours

Cognitive performances and locomotor activity following dentate granule cell damage in rats: Role of lesion extent and type of memory tested

Intradentate injection of colchicine is one of the techniques used to destroy granule cells. This study compared the behavioral effects of various amounts of colchicine (1.0, 3.0, and 6.0 microg; Col 1, Col 3, and Col 6, respectively) injected into the dentate gyrus of adult Long-Evans male rats. Starting 10 days after lesion surgery, behavioral testing assessed home-cage and open-field locomotion, alternation in a T-maze, water-maze, and radial-maze learning according to protocols placing emphasis on reference, and working memory. All of these tasks are sensitive to hippocampal disruption. Histological verifications showed that the extent of the lesions depends on the dose of colchicine (index of dentate gyrus shrinkage: -33% in Col 1, -54% in Col 3, and -67% in Col 6 rats). Colchicine dose-dependently increased nocturnal home cage activity (an effect found 10 days but not 5 months after surgery), but had no significant effect on open-field locomotion or T-maze alternation. A dose-dependent reference memory impairment was found during the acquisition of spatial navigation in the water maze; Col 3 and Col 6 rats were more impaired than Col 1 rats. During the probe trial (platform removed), control rats spent a longer distance swimming over the platform area than all rats with colchicine lesions. In the working memory version of the test, all rats with colchicine lesions showed significant deficits. The deficits were larger in Col 3 and Col 6 rats compared to Col 1 rats. The lesions had no effect on swimming speed. In the radial-maze test, there was also a dose-dependent working memory impairment. However, reference memory was disrupted in a manner that did not differ among the three groups of lesioned rats. Our data are in line with the view that the dentate gyrus plays an important role in the acquisition of new information and is an integral neural substrate for spatial reference and spatial working memory. They also suggest that damage to granule cells might have more pronounced effects on reference than on working memory in the radial maze. Finally, they demonstrate that part of the variability in the conclusions from previous experiments concerning the role of granule cells in cognitive processes, particularly in spatial learning and memory, may be due to the type of tests used and/or the extent of the damage produced

The fimbria-fornix/cingular bundle pathways: A review of neurochemical and behavioural approaches using lesions and transplantation techniques

Extensive lesions of the fimbria-fornix pathways and the cingular bundle deprive the hippocampus of a substantial part of its cholinergic, noradrenergic and serotonergic afferents and, among several other behavioural alterations, induce lasting impairment of spatial learning and memory capabilities. After a brief presentation of the neuroanatomical organization of the hippocampus and the connections relevant to the topic of this article, studies which have contributed to characterize the neurochemical and behavioural aspects of the fimbria-fornix lesion "syndrome" with lesion techniques differing by the extent, the location or the specificity of the damage produced, are reviewed. Furthermore, several compensatory changes that may occur as a reaction to hippocampal denervation (sprouting changes in receptor sensitivity and modifications of neurotransmitter turnover in spared fibres) are described and discussed in relation with their capacity (or incapacity) to foster recovery from the lesion-induced deficits. According to this background, experiments using intrahippocampal or "parahippocampal" grafts to substitute for missing cholinergic, noradrenergic or serotonergic afferents are considered according to whether the reported findings concern neurochemical and/or behavioural effects. Taken together, these experiments suggest that appropriately chosen fetal neurons (or other cells such as for instance, genetically-modified fibroblasts) implanted into or close to the denervated hippocampus may substitute, at least partially, for missing hippocampal afferents with a neurochemical specificity that closely depends on the neurochemical identity of the grafted neurons. Thereby, such grafts are able not only to restore some functions as they can be detected locally, namely within the hippocampus, but also to attenuate some of the behavioural (and other types of) disturbances resulting from the lesions. In some respects, also these graft-induced behavioural effects might be considered as occurring with a neurochemically-defined specificity. Nevertheless, if a graft-induced recovery of neurochemical markers in the hippocampus seems to be a prerequisite for also behavioural recovery to be observed, this neurochemical recovery is neither the one and only condition for behavioural effects to be expressed, nor is it the one and only mechanism to account for the latter effects

PLoS ONE

Although many clinical pathological states are now detectable using imaging and biochemical analyses, neuropsychological tests are often considered as valuable complementary approaches to confirm diagnosis, especially for disorders like Alzheimer's or Parkinson's disease, and schizophrenia. The touchscreen-based automated test battery, which was introduced two decades ago in humans to assess cognitive functions, has recently been successfully back-translated in monkeys and rodents. We focused on optimizing the protocol of three distinct behavioral paradigms in mice: two variants of the Paired Associates Learning (PAL) and the Visuo-Motor Conditional Learning (VMCL) tasks. Acquisition of these tasks was assessed in naive versus pre-trained mice. In naive mice, we managed to define testing conditions allowing significant improvements of learning performances over time in the three aforementioned tasks. In pre-trained mice, we observed differential acquisition rates after specific task combinations. Particularly, we identified that animals previously trained in the VMCL paradigm subsequently poorly learned the sPAL rule. Together with previous findings, these data confirm the feasibility of using such behavioral assays to evaluate the power of different models of cognitive dysfunction in mice. They also highlight the risk of interactions between tasks when rodents are run through a battery of different cognitive touchscreen paradigms

Intraseptal infusions of 8-OH-DPAT in the rat impairs water-maze performances: effects on memory or anxiety?

In the rat, 5-HT1A receptors are found on medial septal cholinergic neurons. The effects of intraseptal infusions of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-amino)-tertralin) were assessed on reference memory performances in a water maze. Compared with vehicle infusions, 0.5 and 4 microg of 8-OH-DPAT significantly impaired (but did not prevent) acquisition of the task and probe-trial performances. The results suggest that activation of 5-TH1A receptors in the (medial) septal area impairs spatial learning, perhaps directly by reducing the hippocampal cholinergic tonus, or indirectly by an effect on anxiety

Effects of 192 IgG-saporin on acetylcholinesterase histochemistry in male and female rats

Sex hormones may exert neuroprotective effects in various models of brain lesions. Male and female Long-Evans rats were subjected to intracerebroventricular injections of 2 microg 192 IgG-saporin or vehicle. Starting 2 days before surgery, half the male rats were treated with estradiol for 7 days. Three weeks after surgery, they were sacrificed for histochemical staining of acetylcholinesterase (AChE) and densitometric evaluations. The lesion induced a substantial to dramatic decrease of the AChE-positive fiber density in the cingulate, somatosensory, piriform, retrosplenial and perirhinal cortices, and in the hippocampus. Weak effects were found in the striatum. There was no significant decrease in the dorsal thalamus. Sex had no significant effect on AChE-positive staining in any brain area. In males, estradiol treatment did not alter the effects of 192 IgG-saporin. These results show that sex or estradiol treatment in male rats does not interfere with the immunotoxic effects of intracerebroventricular injections of 192 IgG-saporin on cholinergic projections from the basal forebrain

Downregulation of muscarinic- and 5-HT1B-mediated modulation of [3H]acetylcholine release in hippocampal slices of rats with fimbria-fornix lesions and intrahippocampal grafts of septal origin

Adult Long-Evans female rats sustained electrolytic fimbria-fornix lesions and, two weeks later, received intrahippocampal suspension grafts of fetal septal tissue. Sham-operated and lesion-only rats served as controls. Between 6.5 and 8 months after grafting, both the [3H]choline accumulation and the electrically evoked [3H]acetylcholine ([3H]ACh) release were assessed in hippocampal slices. The release of [3H]ACh was measured in presence of atropine (muscarinic antagonist, 1 microM), physostigmine (acetylcholinesterase inhibitor, 0.1 microM), oxotremorine (muscarinic agonist, 0.01 microM-10 microM), mecamylamine (nicotinic antagonist, 10 microM), methiothepin (mixed 5-HT1/5-HT2 antagonist, 10 microM), 8-OH-DPAT (5-HT1A agonist, 1 microM), 2-methyl-serotonin (5-HT3 agonist, 1 microM) and CP 93129 (5-HT1B agonist, 0.1 microM-100 microM), or without any drug application as a control. In lesion-only rats, the specific accumulation of [3H]choline was reduced to 46% of normal and the release of [3H]ACh to 32% (nCi) and 43% (% of tissue tritium content). In the grafted rats, these parameters were significantly increased to 63%, 98% and 116% of control, respectively. Physostigmine reduced the evoked [3H]ACh release and was significantly more effective in grafted (-70%) than in sham-operated (-56%) or lesion-only (-54%) rats. When physostigmine was superfused throughout, mecamylamine had no effect. Conversely, atropine induced a significant increase of [3H]ACh release in all groups, but this increase was significantly larger in sham-operated rats (+209%) than in the other groups (lesioned: +80%; grafted: +117%). Oxotremorine dose-dependently decreased the [3H]ACh release, but in lesion-only rats, this effect was significantly lower than in sham-operated rats. Whatever group was considered, 8-OH-DPAT, methiothepin and 2-methyl-serotonin failed to induce any significant effect on [3H]ACh release. In contrast, CP 93129 dose-dependently decreased [3H]ACh release. This effect was significantly weaker in grafted rats than in the rats of the two other groups. Our data confirm that cholinergic terminals in the intact hippocampus possess inhibitory muscarinic autoreceptors and serotonin heteroreceptors of the 5-HT1B subtype. They also show that both types of receptors are still operative in the cholinergic terminals which survived the lesions and in the grafted cholinergic neurons. However, the muscarinic receptors in both lesioned and grafted rats, as well as the 5-HT1B receptors in grafted rats show a sensitivity which seems to be downregulated in comparison to that found in sham-operated rats. In the grafted rats, both types of downregulations might contribute to (or reflect) an increased cholinergic function that results from a reduction of the inhibitory tonus which ACh and serotonin exert at the level of the cholinergic terminal

Shifting between response and place strategies in maze navigation: effects of training, cue availability and functional inactivation of striatum or hippocampus in rats

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