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The cholinergic basal forebrain system during development and its influence on cognitive processes: important questions and potential answers.

This review seeks to address, though perhaps not answer fully, four important questions about the cholinergic basal forebrain (BF) system in developing mammals. First, what role does the cholinergic basal forebrain system play in the development of cognitive functions? Second, does the cholinergic BF system play a fundamentally similar role in development vs. adulthood? Third, does sexual dimorphism of the developing cholinergic BF system influence cognition differently in the two sexes? Finally, what role does the developing cholinergic BF system play in developmental disorders such as Down syndrome and Rett syndrome? Examples from the literature, primarily studies in mice and rats, are given in an attempt to answer these important questions.

Acetylcholine↗

Modulation of anxiety-like behavior and morphine dependence in CREB-deficient mice.

The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Crebl(NesCre)). A genetically defined cohort of the previously described hypomorphic Crebl(alphadelta) mice, in which the two major transcriptionally active isoforms (alpha and delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.

Analysis of Variance↗

The effect of interviewer bias on mental illness questionnaire responses.

The purpose of this study was to investigate how interviewer behavior affects information obtained from a respondent during an interview. The five factors of interviewer behavior that were studied were social reinforcement, interviewer disclosure, verbal modeling, interviewer dress, and seating arrangement. The dependent variable was the number of symptoms reported on the 22-item Mental Health Inventory. A total of 128 male and female adult patients under treatment for mental illness were interviewed under procedures using all combinations of the five factors. Control of patient sex, age, ethnicity, and education was effected through the use of a balanced design. The results demonstrated that the behavior of the interviewer influenced the respondent's report of psychiatric symptoms. The largest number of psychiatric symptoms were reported when the interviewer gave social reinforcement while wearing a lab coat and sitting across a desk from the respondent.

Adult↗

Influence of path integration versus environmental orientation on place cell remapping between visually identical environments.

To assess the effects of interactions between angular path integration and visual landmarks on the firing of hippocampal neurons, we recorded from CA1 pyramidal cells as rats foraged in two identical boxes with polarizing internal cues. In the same-orientation condition, following an earlier experiment by Skaggs and McNaughton, the boxes were oriented identically and connected by a corridor. In the opposite-orientation condition, the boxes were abutted by rotating them 90 degrees in opposite directions, so that their orientations differed by 180 degrees . After 16-23 days of pretraining on the same-orientation condition, three rats experienced both conditions in counterbalanced order on each of two consecutive days. On the third day they ran two opposite-orientation trials. Although Skaggs and McNaughton observed stable partial "remapping" of place fields, none of the fields in this experiment remapped in the same-orientation condition. In the opposite-orientation condition, place fields in the first box were isomorphic with those in the same-orientation condition, whereas in the second box the rats eventually exhibited completely different fields. The rats differed as to the trial in which this first occurred. Once the second box exhibited different fields, it continued to do so in all subsequent opposite-orientation trials, yet fields remained the same in subsequent same-orientation trials. The results demonstrate that when animals move actively between environments, and are thus potentially able to maintain their inertial angular orientation, discordance between environmental orientation and the rat's idiothetic direction sense can profoundly affect the hippocampal map-either immediately, or as a result of cumulative experience.

Analysis of Variance↗

Feature-based wavelet shrinkage algorithm for image denoising.

A selective wavelet shrinkage algorithm for digital image denoising is presented. The performance of this method is an improvement upon other methods proposed in the literature and is algorithmically simple for large computational savings. The improved performance and computational speed of the proposed wavelet shrinkage algorithm is presented and experimentally compared with established methods. The denoising method incorporated in the proposed algorithm involves a two-threshold validation process for real-time selection of wavelet coefficients. The two-threshold criteria selects wavelet coefficients based on their absolute value, spatial regularity, and regularity across multiresolution scales. The proposed algorithm takes image features into consideration in the selection process. Statistically, most images have regular features resulting in connected subband coefficients. Therefore, the resulting subbands of wavelet transformed images in large part do not contain isolated coefficients. In the proposed algorithm, coefficients are selected due to their magnitude, and only a subset of those selected coefficients which exhibit a spatially regular behavior remain for image reconstruction. Therefore, two thresholds are used in the coefficient selection process. The first threshold is used to distinguish coefficients of large magnitude and the second is used to distinguish coefficients of spatial regularity. The performance of the proposed wavelet denoising technique is an improvement upon several other established wavelet denoising techniques, as well as being computationally efficient to facilitate real-time image-processing applications.

Algorithms↗

Circadian phase-shifted rats show normal acquisition but impaired long-term retention of place information in the water task.

It is thought that circadian rhythms may influence learning and memory processes. However, research supporting this view does not dissociate a mnemonic impairment from other performance deficits. Furthermore, published reports do not specify the type of memory system influenced by the circadian system. The present study assessed the effects of phase shifting on acquisition and expression of place navigation in the water maze, a task sensitive to hippocampal dysfunction. The results showed that phase-shifting circadian rhythms in rats impaired the expression of place information on a retention test but not initial acquisition or encoding of place information. These results suggest that disruption of circadian rhythms may impair consolidation of previously encoded hippocampal place information.

Animals↗

Aversive properties of naloxone in non-dependent (naive) rats may involve blockade of central beta-endorphin.

The present study examines the influence of destruction of the medio-basal arcuate hypothalamus (MBH), the primary site of synthesis of central pools of beta-endorphin (beta-EP), upon the aversive properties of naloxone in a conditioned place preference paradigm. Bilateral radiofrequency lesions of the MBH resulted in a pronounced fall in levels of immunoreactive beta-EP in the brain. Lesioned rats, in contrast to non-operated animals, showed a clear reduction in the conditioned place aversion produced by naloxone. However, they showed no loss of the conditioned preference produced by the mu-selective opioid receptor agonist, morphine, or the conditioned aversion produced by the kappa-selective agonist, U50-488. In contrast to the effect of the lesions, suppression of circulating beta-EP by dexamethasone treatment failed to influence conditioning produced by naloxone. Thus, the data indicate that the aversive properties of naloxone are attenuated by disruption of central (but not peripheral) beta-EP activity. We suggest that these properties of naloxone reflect an antagonism of beta-EP activity in the brain. In addition, the data indicate that differing mechanisms underlie the aversive actions of naloxone as compared to U50-488.

Animals↗

Non-visual environmental imaging and object detection through active electrolocation in weakly electric fish.

Weakly electric fish orient at night by employing active electrolocation. South American and African species emit electric signals and perceive the consequences of these emissions with epidermal electroreceptors. Objects are detected by analyzing the electric images which they project onto the animal's electroreceptive skin surface. Electric images depend on size, distance, shape, and material of objects and on the morphology of the electric organ and the fish's body. It is proposed that the mormyrid Gnathonemus petersii possesses two electroreceptive "foveae" at its Schnauzenorgan and its nasal region, both of which resemble the visual fovea in the retina of many animals in design, function, and behavioral use. Behavioral experiments have shown that G. petersii can determine the resistive and capacitive components of an object's complex impedance in order to identify prey items during foraging. In addition, fish can measure the distance and three-dimensional shape of objects. In order to determine object properties during active electrolocation, the fish have to determine at least four parameters of the local signal within an object's electric image: peak amplitude, maximal slope, image width, and waveform distortions. A crucial parameter is the object distance, which is essential for unambiguous evaluation of object properties.

Animals↗

A behavioral profile of autoimmune lupus-prone MRL mice.

Manifestations of the human autoimmune disease systemic lupus erythematosus (SLE) include a number of behavioral and cognitive deficits. The present study asks whether neurobehavioral dysfunction is present also in MRL mice that spontaneously develop most of the fundamental immunological aberrations of SLE. There are two congenic substrains of MRL mice that differ in the time of disease onset: MRL-lpr mice develop lupus early and MRL(-)+/+ develop the typical signs of disease relatively late in life. The behavior of these substrains was assessed at 7 to 11 weeks of age, a time that coincides with the onset of disease in MRL-lpr mice and the absence of known lupus symptoms in the MRL(-)+/+ group. When compared to the congenic MRL(-)+/+ control substrain, MRL-lpr mice were spontaneously less active, traversed a crossbeam slower, and ceased responding to the novelty of a new environment sooner. They were also more reluctant to leave their home base or travel far away from it and perseverated in their response bias during extinction and reversal learning. Immunological status was characterized by moderate proteinuria in both substrains and high titers of antinuclear antibodies in MRL-lpr but not MRL(-)+/+ mice. Histological analysis revealed minimal or no signs of joint pathology in MRL-lpr mice. Thus, this study shows the presence of behavioral dysfunction in mice with early stages of autoimmune disease and gives support for the idea that MRL mice may provide a useful model of neurobehavioral dysfunction in SLE. It is suggested that the behavioral profile of MRL-lpr mice may indicate increased "timidity," related to genetics, autoimmunity, or both.

Animals↗

Movement-related correlates of single cell activity in the interpeduncular nucleus and habenula of the rat during a pellet-chasing task.

The habenula and interpeduncular nucleus (IPN) are part of a dorsal diencephalic conduction system which receives input from cholinergic, striatal, and hypothalamic areas, and sends output to several, disparate midbrain regions. These output regions include the dorsal tegmental nucleus, which is part of a navigation-related system that provides a signal for directional heading. The habenula and IPN also project to the dorsal and medial Raphe nuclei, thought to be involved in mood and behavioral state regulation. Here, cells in both the habenula and IPN were recorded in freely moving rats while they foraged for food pellets. There were four major findings. First, many of the cells tended to fire in sporadic bouts of relatively high versus low rates, and this may be related to intrinsic cell properties discovered during in vitro studies. Second, although these regions are connected to the direction signaling circuit, they do not, themselves demonstrate a directional signal. Third, about 10% of the cells in the lateral habenula showed a strong correlation between rate and angular head motion. This may constitute an important, requisite input to the above-mentioned head direction circuit. Finally, many of the cells in each region showed a temporally coarse correlation with running speed, so that bouts of high frequency firing coincided with episodes of higher behavioral activation. This last finding may be related to work which shows an influence of the habenula on locomotor activity, and in relation to the protective effects of exercise in relation to stress, as mediated by the Raphe nuclei.

Action Potentials↗

Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice.

Histidine decarboxylase deficient (Hdc(-/-)) and wild-type male mice on the C57Bl6/J background were used to determine the role of histamine in brain function. 3-5 (Y) and 12-14 (MA) month-old Hdc(-/-) mice showed hypoactivity and increased measures of anxiety in the open field, light-dark, elevated plus-maze, and elevated zero maze tests. Y Hdc(-/-) mice showed superior performance in the hidden sessions of the water maze and passive avoidance memory retention. In contrast, Y Hdc(-/-) mice were impaired in novel location recognition, spent less time searching in the target quadrant and more time searching in the outer zone of the water maze during the probe trials. These behaviors are likely due to increased measures of anxiety and are not found in MA Hdc(-/-) mice. These data support a role for histamine in anxiety and cognition and underline the importance of considering age and potential effects on measures of anxiety in the interpretation of the role of histaminergic neurotransmission in cognitive function.

Age Factors↗

Tolerance development to Morris water maze test impairments induced by acute allopregnanolone.

The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2 mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20 mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

Analysis of Variance↗

Medial septum lesions disrupt exploratory trip organization: evidence for septohippocampal involvement in dead reckoning.

Rats organize their open field behavior into a series of exploratory trips focused around a central location or home base. In addition, differences in movement kinematics have been used to fractionate the exploratory trip into tour (i.e., sequences of linear movement or progressions punctuated by stops) and homeward (i.e., single progression direct to the home base) segments. The observation of these characteristics independent of environmental familiarity and visual cue availability has suggested a role for self-movement information or dead reckoning in organizing exploratory behavior. Although previous work has implicated a role for the septohippocampal system in dead reckoning based navigation, as of yet, no studies have investigated the contribution of the medial septum to dead reckoning. First, the present study examined the organization of exploratory behavior under dark and light conditions in control rats and rats receiving either electrolytic or sham medial septum lesions. Medial septum lesions produced a significant increase in homeward segment path circuity and variability of temporal pacing of linear speeds. Second, as an independent assessment of the effectiveness of the medial septum lesions, rats were trained to locate a hidden platform in the standard water maze procedure. Consistent with previous research, medial septum lesions attenuated learning the location of the hidden platform. These results demonstrate a role for the medial septum in organizing exploratory behavior and provide further support for the role of the septohippocampal system in dead reckoning based navigation.

Animals↗

Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1.

Glutamatergic fast synaptic transmission is known to be altered with age in a region-specific manner in hippocampus of memory-impaired old rats. In the present experiment, presynaptic fiber potentials and non-N-methyl-D-aspartate (NMDAR) and NMDAR-mediated synaptic responses in CA1 were compared in three ages of behaviorally characterized male F-344 rats. In the CA1 region, old rats showed approximately equivalent reductions in non-NMDAR- and NMDAR-excitatory postsynaptic potential amplitudes for a given size of presynaptic fiber potential. There was no change in magnitude of the presynaptic response itself at any stimulus level. These results are consistent with the hypothesis that there is a reduction in the number of Schaffer collateral synapses per presynaptic axon. This pattern of results in CA1 is very different from what is known to occur at the perforant path-granule cell synapse. In fascia dentata the non-NMDAR-mediated excitatory postsynaptic potential is increased in amplitude, although the NMDAR-mediated excitatory postsynaptic potential is reduced for a given presynaptic input. These data suggest that age-related functional alterations in neurotransmitter receptor subtypes occur differentially between closely-related anatomical subregions.

Aging↗