Spatial reference memory and neocortical neurochemistry vary with the estrous cycle in C57BL/6 mice.

Estrous cycle-related variations of spatial reference memory and neurochemistry in intact female mice were examined. Spatial reference memory was tested in cycling females, ovariectomized (OVX) females, and males by using a 1-day water maze protocol. Choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activities were measured in the hippocampus and neocortex. Estrus females exhibited worse spatial acquisition and 30-min retention than did proestrus and metestrus females, higher neocortical ChAT activity than proestrus females, and higher neocortical GAD activity than OVX females and males. Neocortical, rather than hippocampal, neurochemistry was more sensitive to hormonal modulation, suggesting that hormonal mediation of neocortical function may play a critical role in regulating spatial reference memory in female mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intraventricular administration of BDNF increases neuropeptide expression in newborn rat brain

Brain-derived neurotrophic factor (BDNF) specifically enhances and maintains the expression of neuropeptide Y (NPY) and somatostatin (SOM) in cultured neocortical neurons (Nawa et al., 1993). In this article, we examined its effects in vivo on neuropeptide expression in various brain regions by injecting BDNF into the cerebroventricle of newborn rats. Repeated administration (2x) of BDNF increased contents of NPY-like immunoreactivity (NPY-LI) and substance P (SP)-LI most markedly in the anterior neocortex by 11- and 24-fold, respectively, in comparison to values in the animals receiving control injection. A smaller but significant increase was also observed in immunoreactivity for somatostatin (SOM), enkephalin (ENK), and cholecystokinin (CCK). mRNA for NPY, SP, and SOM was similarly upregulated in the anterior neocortex, suggesting that BDNF enhances peptide synthesis rather than inhibiting peptide release or degradation. Among the brain regions examined, however, peptidergic responses to BDNF were different with respect to their spatial distribution and time course. Induction of SP-LI, NPY-LI, and SOM-LI around the injection site was most pronounced in cortical layers II/III, layers IV-VI, and layer VI, respectively. Peptidergic immunoreactivity was also enhanced in other brain regions ipsilateral to the injection site, for example, NPY-LI in the hippocampus, thalamic nuclei, and striatum, and SOM-LI in the striatum. A single injection of BDNF elevated SP-LI to a plateau level within 12 hr while NPY-LI and SOM-LI reached maximum levels at 48 hr, and then all returned to control levels at 68 hr. In contrast, the same dose of NGF had no influences on the neuropeptide levels at 48 hr. These observations suggest that BDNF regulates the development of neuropeptide expression in the CNS in a plastic manner.     

A competitive enzyme-linked immunosorbent assay for measuring the levels of serum antibody to Haemophilus influenzae type b

1. The protein family of the neurotrophins, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and Neurotrophin-3, -4/5, and -6 (NT-3; NT-4/5; NT-6) is well known to enhance the survival and to stabilize the phenotype of different populations of neurons in the central and the peripheral nervous system. These effects are mediated via binding to specific tyrosine kinase receptors (Trks) and to the low-affinity p75 neurotrophin receptor. 2. The neurotrophins NGF, BDNF, and NT-3 and the BDNF and NT-3 selective receptors (TrkB, TrkC) are expressed at high levels in neurons of the basal forebrain, the hippocampus, and the neocortex of the mammalian brain. The expression and secretion of NGF and BDNF in these brain areas is regulated by (physiological levels of) neuronal activity. 3. Exogenous application of the neurotrophins to hippocampal and neocortical neurons can enhance excitatory glutamatergic synaptic transmission via activation of Trk receptors. In addition, long-term potentiation (a potential cellular correlate for learning and memory formation in mammals) in the rodent hippocampus depends on endogenous supply of neurons with BDNF. 4. Judged by the analysis of electrophysiological data, the BDNF- and NT-3-induced enhancement of glutamatergic synapses is mediated by increasing the efficacy of glutamate release from the presynaptic neuron. However, neurotrophin-dependent postsynaptic enhancement of NMDA (but not AMPA) receptor responsiveness has also been shown. 5. On the molecular level, neither the pre- nor the postsynaptic modulation of glutamatergic synapses by neurotrophins is well understood. However, neurotrophins were shown to acutely affect intraneuronal Ca2+ levels and to influence molecular components of the transmitter release machinery, which could underly the presynaptic modifications, whereas BDNF-induced phosphorylation of NMDA-type glutamate receptors could account for the postsynaptic effects. 6. Taken together, these results suggest that the activity-dependent release of neurotrophins at frequently used synapses could modulate the synaptic efficacy at these junctions. Thus, neurotrophins might operate as locally released feedback modulators of synaptic transmission, and this could be a cellular correlate for certain aspects of information processing in the mammalian brain.     

Anandamide and other N-acylethanolamines in mouse peritoneal macrophages

Exposure to stressful events and elevated level of stress hormones are associated with impaired spatial memory and neuronal damage in the hippocampus. These neurons are considered to be maintained by neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) and trk family of neurotrophin receptors. Male Wistar rats (6 weeks old) were exposed to immobilization stress for 8 h and their brains were processed for in situ hybridization histochemistry. Exposure to long-lasting immobilization stress reduced mRNA levels for neurotrophins and their high affinity receptors in the brain, especially in the hippocampus. Our results provide, some new information that may be relevant to the pathogenesis of stress-induced disturbances of memory and learning.     

Imaging of hippocampal and neocortical neural activity following intravenous cocaine administration in freely behaving cats

We examined spatial-temporal patterns of neural activity, as inferred from 700 nm light reflectance, from the dorsal hippocampus and surrounding neocortex in seven freely behaving cats following 1.5, 2.5, 3.5 and 5.0 mg/kg intravenous cocaine administration. Images were acquired using a new technique which gathered reflected light from cortical and subcortical structures. Cardiac and respiratory patterning, collected simultaneously with optical images, revealed increased rates and diminished variation after intravenous cocaine administration. Cocaine increased reflectance correlates of hippocampal neural activity in a dose-dependent fashion over a 120 min period, with a lengthening time-to-peak effect (22-76 min). The largest dose resulted in an initial decrease, followed by the greatest enhancement in neuronal activity. Correlates of neural activation in the neocortex displayed an inverse dose-response curve to that found in the hippocampus; the time-to-peak effect was shorter (6-43 min) and the maximal change was reduced. Regional patches and bands of activation occurred during the period of the cocaine response, and were more pronounced in the hippocampus than the neocortex. Procaine, administered in a similar dose, slightly increased neural activity for 10 min in both the hippocampus and neocortex, and elicited a small increase in respiration. Cocaine induces a pronounced enhancement of neural activation in the neocortex and dorsal hippocampus; the time course of activation in the hippocampus parallels an increased respiratory pattern and outlasts the neocortical response. We speculate that hippocampal activation may be related to the profound respiratory acceleration found in response to cocaine.     

The involvement of brain-derived neurotrophic factor in hippocampal long-term potentiation revealed by gene targeting experiments

Brain-derived neurotrophic factor (BDNF) is a member of the NGF gene family, which has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes like long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF-gene. We then used hippocampal slices from these mice to investigate whether LTP is affected by this mutation. Mutant mice showed significantly weaker LTP in the CA1 region. The magnitude of the potentiation as well as the percentage of cases in which LTP could be induced successfully was clearly reduced whereas important pharmacological and morphological control parameters in the hippocampus of these animals were unaffected. Adenoviral vectors were used to re-express BDNF in acute slices of BDNF-knock-out mice. In most cases LTP could be rescued with this approach. These results suggest that BDNF has an important functional role in the expression of LTP in the hippocampus.     

Time-dependent changes in neurotrophic factor mRNA expression after kindling and long-term potentiation in rats

We compared the time-dependent changes in messenger ribonucleic acid (mRNA) levels for two neurotrophic factors after amygdala-kindled seizures and hippocampal long-term potentiation (LTP) in rats in vivo. The brain-derived neurotrophic factor (BDNF) mRNA levels in the bilateral granule cell layer of the dentate gyrus, increased significantly 1-4 h after stage 5 kindled seizures. Nerve growth factor (NGF) mRNA levels increased throughout the bilateral limbic regions more gradually than those of BDNF mRNA. The maximum levels in the dentate gyrus ipsilateral to stimulation (BDNF mRNA: 493%, NGF mRNA: 199% of control levels) occurred 2 h after seizures. As observed with kindling, BDNF and NGF mRNA expression increased in the dentate gyrus ipsilateral to stimulation also increased following LTP induced by the perforant path stimulation, with maximum levels occurring 2 h and 4 h, respectively, after stimulation, when they reached 284% and 189% of the control levels, respectively. These results suggest that BDNF and NGF are involved in enhancement of synaptic efficacy in the granule cells of the dentate gyrus in the hippocampus in kindling, not related to the neuronal excitability associated with seizure activity.     

Single enrichment variables differentially reduce age-related memory decline in female mice.

The authors sought to determine how different elements of enrichment, for example, cognitive stimulation and voluntary exercise, differ in their ability to improve memory throughout the lifespan. Young, middle-aged, and aged female C57BL/6 mice received 24-hr exposure in their home cages to toys alone (cognitive stimulation), running wheels alone (exercise), or both toys and running wheels (complex enrichment) for 4 weeks prior to and then throughout spatial water maze testing. As expected, spatial memory became progressively worse with age. Exercise alone improved spatial water maze performance in young mice, whereas both exercise alone and complex enrichment improved spatial maze performance in middle-aged mice. All enrichment treatments improved spatial maze performance in aged mice. These data suggest that exercise is the most effective element of enrichment in young female mice and that both cognitive stimulation and exercise are necessary to reliably improve spatial water maze performance in aging female mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats

Traumatic brain injury (TBI) results in chronic derangements in central cholinergic neurotransmission that may contribute to posttraumatic memory deficits. Intraventricular cannula (IVC) nerve growth factor (NGF) infusion can reduce axotomy-induced spatial memory deficits and morphologic changes observed in medial septal cholinergic neurons immunostained for choline acetyltransferase (ChAT). We examined the efficacy of NGF to (1) ameliorate reduced posttraumatic spatial memory performance, (2) release of hippocampal acetylcholine (ACh), and (3) ChAT immunoreactivity in the rat medial septum. Rats (n = 36) were trained prior to TBI on the functional tasks and retested on Days 1-5 (motor) and on Day 7 (memory retention). Immediately following injury, an IVC and osmotic pump were implanted, and NGF or vehicle was infused for 7 days. While there were no differences in motor performance, the NGF-treated group had significantly better spatial memory retention (P < 0.05) than the vehicle-treated group. The IVC cannula was then removed on Day 7, and a microdialysis probe was placed into the dorsal hippocampus. After a 22-h equilibration period, samples were collected prior to and after administration of scopolamine (1 mg/kg), which evoked ACh release by blocking autoreceptors. The posttraumatic reduction in scopolamine-evoked ACh release was completely reversed with NGF. Injury produced a bilateral reduction in the number and cross-sectional area of ChAT immunopositive medial septal neurons that was reversed by NGF treatment. These data suggest that cognitive but not motor deficits following TBI are, in part, mediated by chronic deficits in cholinergic systems that can be modulated by neurotrophic factors such as NGF.     

Brain-derived neurotrophic factor and neurotrophin-4 increase neurotrophin-3 expression in the rat hippocampus

Hippocampal levels of mRNA encoding nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are rapidly induced by enhanced neuronal activity following seizures and glutamate or muscarinic receptor activation. However, the levels of neurotrophin-3 (NT-3) mRNA acutely decrease after limbic seizures suggesting that a different mode of regulation may exist for these neurotrophins. Here we show that BDNF and neutrotrophin-4 (NT-4), but not NT-3 itself, up-regulate NT-3 mRNA in cultured hippocampal neurons. In the rat hippocampus, the muscarinic receptor agonist, pilocarpine increased BDNF mRNA levels rapidly and those of NT-3 with a delay of several hours. Injection of BDNF into neonatal rats elevated NT-3 mRNA in the hippocampus which demonstrates that BDNF is able to enhance NT-3 expression in vivo. The regulation of NT-3 by BDNF and NT-4 enlargens the neurotrophic spectrum of these neurotrophins to include neuron populations responsive primarily to NT-3.     

An enhanced conversion from tightly bound to loosely bound form of NGF in selected regions of brains from male mice

Most of the nerve growth factor (NGF) protein in the rat and mouse brain is readily extractable in the presence of guanidine hydrochloride as is the case of brain-derived neurotrophic factor. In the present study, we measured amounts of NGF that could be extracted in the presence and absence of 1 M guanidine hydrochloride from various regions of the brains of male and female mice. About 14% of the total NGF in the hippocampus from female mice at 4 months of age could be extracted without 1 M guanidine hydrochloride (designated loosely bound NGF; about 32% in the rat hippocampus) and the remainder only in its presence (designated tightly bound NGF). The molecular masses of the NGF-immunoreactive protein in both cases were approximately 14 kDa. There were significant differences in respective concentrations of total NGF (the loosely bound plus tightly bound NGF) in the hypothalamus and hypophysis, but not in other brain regions, between male and female mice at 4 months of age. However, levels of loosely bound NGF in the cerebellum and olfactory bulb from males were significantly higher than those in the same regions from females. This difference resulted in two-fold higher ratios of the concentrations of loosely bound to total NGF in males as compared to females. On the other hand, the ratio in the hypophysis was close to unity in both sexes. The concentrations of loosely bound NGF in the hippocampus and cerebral cortex decreased slightly with age in both males and females. Levels of loosely bound NGF increased significantly from 2 to 12 months after birth in the whole brain, olfactory bulb, cerebellum, hypothalamus and hypophysis to a greater extent in males than in females. Thus, it is suggested that high ratios of loosely bound to total NGF in selected regions of brains from male mice are due to an enhanced conversion from tightly to loosely bound form, which is considered to be regulated by androgens (see Brain Res. 322, 112-117, 1990). They may also influence the total NGF expression.     

Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance?

Brain-derived neurotrophic factor (BDNF) promotes neuron survival, enhances sprouting, protects neurons against insult, and may be involved in several aspects of learning and memory. In this study, rats trained to locate a submerged platform in a water maze had elevated levels of BDNF messenger ribonucleic acid (mRNA) in the hippocampus (p < .05), a structure associated with spatial memory. BDNF mRNA expression increased after 3 and 6 days but not after 1 day of training in the water maze. A yoked control group that swam without the platform present, to control for physical activity, showed a trend for elevated BDNF mRNA at an intermediate level between the learning and sedentary groups. Other cortical and subcortical areas did not show a significant increase in BDNF mRNA after learning or activity (p > .05). These findings suggest that learning can impact BDNF mRNA expression localized to the brain areas involved in the processing of spatial information. Furthermore, behaviors such as physical activity and learning may help maintain and protect neurons at risk in aging and neurodegenerative disease via increased BDNF expression.     

Hippocampal contributions to cortical plasticity

The hippocampal complex and neocortex are both integrally important in memory function, in particular as regards memory for episodes and knowledge about the world that is derived from them. It is traditionally assumed that the role of the hippocampus is time-limited, after which retrieval of episodic memory depends only upon neocortical stores. A number of lines of evidence indicate that this traditional view is incorrect. We propose that the hippocampal complex is always necessary for retrieval of episodes and their contextual frame, and that hippocampal-neocortical interactions contribute instead to the extraction of semantic information to be stored in the neocortex.     

Immunohistochemical study of Ulex europaeus agglutinin 1 (UEA-1) binding of megakaryocytes in bone marrow biopsy specimens: demonstration of heterogeneity in staining pattern reflecting the stages of differentiation

Age-related spatial memory deficits are correlated with septohippocampal cholinergic system degeneration. The present study examined the effect of intraseptal infusions of the cholinergic agonist, oxotremorine, on spatial reference memory in middle-aged rats using place discrimination in the water maze, and on cholinergic activity using choline acetyltransferase (ChAT) activity. Oxotremorine mildly improved the rate of place discrimination acquisition of middle-aged rats during initial sessions only, but did not affect asymptotic levels of performance achieved. Of the brain regions assayed, ChAT activity increased with age in the temporal cortex and dorsal CA2/3 region of the hippocampus. Oxotremorine significantly decreased ChAT activity in the dorsal hippocampus. In contrast to our previous results in aged rats indicating a more robust effect of oxotremorine on spatial working memory, the present results suggest a modest effect of intraseptal oxotremorine on the acquisition of a spatial reference memory task.     

The "Swedish" mutation of the amyloid precursor protein (APPswe) dissociates components of object-location memory in aged Tg2576 mice.

Aged Tg2576 mice show abnormalities in hippocampal morphology and physiology and display behavioral deficits in spatial navigation tasks consonant with a deficit in the functional properties of the hippocampus. However, the nature of the spatial representations disrupted by the "Swedish" mutation of the amyloid precursor protein (APPswe) is unclear. In an effort to characterize the memory deficits in Tg2576 mice, the spontaneous object exploration paradigm was used to interrogate spatial and object memory in mice. With object arrays of comparable size, 16-month-old Tg2576 mice showed a normal object familiarity/novelty effect but impaired memory for the location of objects when 2 objects exchanged locations (topological transformation; Experiment 1). In contrast, Tg2576 mice showed preferential exploration of familiar objects when they were moved to previously unoccupied locations (Experiment 2), irrespective of whether the transformation altered the metric properties of the object array (Experiments 3). These results suggest that Tg2576 mice are able to form representations of the identity of objects and a memory of the spatial organization of objects in an arena. In contrast, conjunctive memory for specific object-location associations is severely impaired in aged Tg2576 mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functionally dissociating aspects of event memory: the effects of combined perirhinal and postrhinal cortex lesions on object and place memory in the rat

Reciprocal interactions between the hippocampus and the perirhinal and parahippocampal cortices form core components of a proposed temporal lobe memory system. For this reason, the involvement of the hippocampus in event memory is thought to depend on its connections with these cortical areas. Contrary to these predictions, we found that NMDA-induced lesions of the putative rat homologs of these cortical areas (perirhinal plus postrhinal cortices) did not impair performance on two allocentric spatial tasks highly sensitive to hippocampal dysfunction. Remarkably, for one of the tasks there was evidence of a facilitation of performance. The same cortical lesions did, however, disrupt spontaneous object recognition and object discrimination reversal learning but spared initial acquisition of the discrimination. This pattern of results reveals important dissociations between different aspects of memory within the temporal lobe. Furthermore, it shows that the perirhinal-postrhinal cortex is not a necessary route for spatial information reaching the hippocampus and that object familiarity-novelty detection depends on different neural substrates than do other aspects of event memory.     

Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR

The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innervation and NT-3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.     

Effects of selective neonatal hippocampal lesions on tests of object and spatial recognition memory in monkeys.

Earlier studies in monkeys have reported mild impairment in recognition memory after nonselective neonatal hippocampal lesions. To assess whether the memory impairment could have resulted from damage to cortical areas adjacent to the hippocampus, we tested adult monkeys with neonatal focal hippocampal lesions and sham-operated controls in three recognition tasks: delayed nonmatching-to-sample, object memory span, and spatial memory span. Further, to rule out that normal performance on these tasks may relate to functional sparing following neonatal hippocampal lesions, we tested adult monkeys that had received the same focal hippocampal lesions in adulthood and their controls in the same three memory tasks. Both early and late onset focal hippocampal damage did not alter performance on any of the three tasks, suggesting that damage to cortical areas adjacent to the hippocampus was likely responsible for the recognition impairment reported by the earlier studies. In addition, given that animals with early and late onset hippocampal lesions showed object and spatial recognition impairment when tested in a visual paired comparison task, the data suggest that not all object and spatial recognition tasks are solved by hippocampal-dependent memory processes. The current data may not only help explain the neural substrate for the partial recognition memory impairment reported in cases of developmental amnesia, but they are also clinically relevant given that the object and spatial memory tasks used in monkeys are often translated to investigate memory functions in several populations of human infants and children in which dysfunction of the hippocampus is suspected. (PsycINFO Database Record (c) 2011 APA, all rights reserved)