Activity Of Basal Forebrain Neurons Research Articles

Cognitive Deficits in Aging Related to Changes in Basal Forebrain Neuronal Activity.

Aging is a physiological process accompanied by a decline in cognitive performance. The cholinergic neurons of the basal forebrain provide projections to the cortex that are directly engaged in many cognitive processes in mammals. In addition, basal forebrain neurons contribute to the generation of different rhythms in the EEG along the sleep/wakefulness cycle. The aim of this review is to provide an overview of recent advances grouped around the changes in basal forebrain activity during healthy aging. Elucidating the underlying mechanisms of brain function and their decline is especially relevant in today's society as an increasingly aged population faces higher risks of developing neurodegenerative diseases such as Alzheimer's disease. The profound age-related cognitive deficits and neurodegenerative diseases associated with basal forebrain dysfunction highlight the importance of investigating the aging of this brain region.

A frontal cortex event-related potential driven by the basal forebrain.

Event-related potentials (ERPs) are widely used in both healthy and neuropsychiatric conditions as physiological indices of cognitive functions. Contrary to the common belief that cognitive ERPs are generated by local activity within the cerebral cortex, here we show that an attention-related ERP in the frontal cortex is correlated with, and likely generated by, subcortical inputs from the basal forebrain (BF). In rats performing an auditory oddball task, both the amplitude and timing of the frontal ERP were coupled with BF neuronal activity in single trials. The local field potentials (LFPs) associated with the frontal ERP, concentrated in deep cortical layers corresponding to the zone of BF input, were similarly coupled with BF activity and consistently triggered by BF electrical stimulation within 5-10 msec. These results highlight the important and previously unrecognized role of long-range subcortical inputs from the BF in the generation of cognitive ERPs. DOI: http://dx.doi.org/10.7554/eLife.02148.001.

Orexins Increase Cortical Acetylcholine Release and Electroencephalographic Activation through Orexin-1 Receptor in the Rat Basal Forebrain during Isoflurane Anesthesia

Cholinergic arousal system plays an important role in the maintenance of consciousness. The authors investigated whether the intrabasalis injection of orexin-A or orexin-B and the electrically stimulated pedunculopontine tegmentum nuclei (PPTg: the origin of cholinergic ascending pathways) may alter acetylcholine efflux and electroencephalographic activity in the somatosensory cortex in relation to the orexinergic system in isoflurane-anesthetized rats. Either orexin-A (10, 30, or 100 pmol) or orexin-B (10, 30, or 100 pmol) (n = 6 each) was injected into the basal forebrain while the electroencephalogram was measured during 1.0 minimum alveolar concentration (1.2%) isoflurane anesthesia. Injection of Ringer's solution was used as a control. The PPTg was electrically stimulated twice with the following conditions: 1-s stimulus train (0.2 ms, 100 Hz, 400 microA) per min for 20 min. Twenty minutes before the second PPTg stimulation, Ringer's solution or 20 microg SB334867, an orexin-1 receptor antagonist (n = 5 each) was injected into the basal forebrain. Injection of orexin-A (30 and 100 pmol) and orexin-B (100 pmol) significantly increased the acetylcholine efflux in the somatosensory cortex (P < 0.05). Injection of orexin-A (10, 30, 100 pmol) and orexin-B (30, 100 pmol) changed the burst and suppression patterns to arousal electroencephalogram. Compared with orexin-B, injection of a lower dose of orexin-A induced increase in the acetylcholine efflux and arousal electroencephalogram. SB334867 significantly attenuated the increases in the acetylcholine efflux and electroencephalographic activation evoked by PPTg stimulation. The authors demonstrated that orexin-A was more potent than orexin-B in producing alteration of cholinergic basal forebrain neuronal activity and that the cortical activation induced by the PPTg stimulation against isoflurane anesthesia may be mediated through the orexin-1 receptors in the basal forebrain.

Effect of cortical spreading depression on basal forebrain neurons

During natural sleep and anesthesia, rhythmic hypo- and hyperpolarizations alternate in cortical pyramidal cells and are reflected as slow (<1 Hz) cortical rhythm at the level of the electroencephalogram (EEG). Membrane potential changes in pyramidal neurons were initially attributed to the rhythmic fluctuation of the cholinergic input as the basal forebrain (BF) neurons fire in synchrony with cortical waves, but a more recent proposal suggested that the slow rhythm was of cortical origin. In the present experiments, interaction between the cortex and the BF was examined in urethane-anesthetized rats. BF neuronal activity was inhibited by local infusion of lidocaine into the substantia innominata in one group of rats, while in another group, the slow cortical rhythm was blocked by inducing spreading depression (SD) in the cortex. Slow cortical rhythm persisted after unilateral lidocaine injection, but rhythmic firing in BF neurons disappeared following SD induction. These findings support the view that slow cortical rhythm is generated in the cortex and transmitted to the BF through descending fibers. According to anatomical data, these fibers can excite cholinergic cells only indirectly as they terminate on non-cholinergic neurons. Thus, timing of activity changes in BF neurons during the slow cortical rhythm might give some clue regarding their transmitter specificity.

Effects of intra-accumbens infusions of amphetamine or cis-flupenthixol on sustained attention performance in rats

Attentional abilities, as reflected by performance in sustained, selective, or divided attention tasks, have been extensively demonstrated to depend on the integrity of cortical cholinergic inputs and their basal forebrain afferent circuits. As nucleus accumbens (NAC) efferent projections have been hypothesized to modulate the excitability of basal forebrain corticopetal projections, the effects of drug-induced modulation of NAC dopaminergic transmission on sustained attention performance in rats were assessed. Unexpectedly, bilateral infusions of amphetamine (AMPH; 0, 3.0, 10.0, 30.0 μg/μl/hemisphere) into the shell region of the NAC did not affect sustained attention performance. In contrast, microinjections of the non-selective dopamine (DA) receptor antagonist cis-flupenthixol (FLU; 0, 3.0, 10.0, 25.0 μg/μl/hemisphere) into the NAC of a separate group of animals impaired the detection of both signals and non-signals, as reflected by decreases in the relative numbers of hits and correct rejections. As the effects of neither AMPH nor FLU followed the predictions made on the basis of current hypotheses about the modulation of basal forebrain neuronal activity by NAC DA, the present results challenge such hypotheses and indicate that the conditions which implicate NAC DA in attentional performance remain unsettled.

Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis.

1. The cholinergic system of the basal forebrain (BF) is hypothesized to play an important role in behavioural and electrocortical arousal. Adenosine has been proposed as a sleep-promoting substance that induces sleep by inhibiting cholinergic neurons of the BF and brainstem. However, adenosinergic influences on the activity of BF neurons in naturally awake and sleeping animals have not been demonstrated. 2. We recorded the sleep-wake discharge profile of BF neurons and simultaneously assessed adenosinergic influences on wake- and sleep-related activity of these neurons by delivering adenosinergic agents adjacent to the recorded neurons with a microdialysis probe. Discharge rates of BF neurons were recorded through two to three sleep-wake episodes during baseline (artificial cerebrospinal fluid perfusion), and after delivering an adenosine transport inhibitor (s-(p-nitrobenzyl)-6-thioinosine; NBTI), or exogenous adenosine, or a selective adenosine A1 receptor antagonist (8-cyclopentyl-1, 3-dimethylxanthine; CPDX). 3. NBTI and adenosine decreased the discharge rate of BF neurons during both waking and non-rapid eye movement (NREM) sleep. In contrast, CPDX increased the discharge rate of BF neurons during both waking and NREM sleep. These results suggest that in naturally awake and sleeping animals, adenosine exerts tonic inhibitory influences on BF neurons, supporting the hypothesized role of adenosine in sleep regulation. 4. However, in the presence of exogenous adenosine, NBTI or CPDX, BF neurons retained their wake- and sleep-related discharge patterns, i.e. still exhibited changes in discharge rate during transitions between waking and NREM sleep. This suggests that other neurotransmitters/neuromodulators also contribute to the sleep-wake discharge modulation of BF neurons.

Phasic relationship between the activity of basal forebrain neurons and cortical EEG in urethane-anesthetized rat

Previous studies have shown that a large number of neurons in the basal forebrain have higher firing rates when the cortical electroencephalogram (EEG) is characterized by low-voltage fast activity compared to states characterized by slow waves. A smaller number of cells with increased discharge rates during slow waves have also been observed. This putative ascending effect is thought to be tonic, but no attempt has been made to analyze a closer temporal correlation between the activity of basal forebrain neurons and the cortical EEG. Recordings were made from single units in the basal forebrain concurrently with the cortical EEG in urethane-anesthetized rats. A total of 52 neurons consistently showed higher firing during low-voltage fast activity (F-cells), whereas 14 neurons were consistently more active during cortical slow waves (S-cells). In most of the F- (90%) and S-cells (86%) the change in firing rate occurred prior to the change in the EEG. The average delay was 300–400 ms. At a deep level of anesthesia, the EEG was characterized by an alternation of flat periods and large waves. Most F-cells became active near the start of the first large wave, which is known to correspond to the onset of depolarization of cortical pyramidal neurons. In contrast, most S-cells were less active during the large waves. These data show that the activity of basal forebrain neurons is phasically correlated with the EEG in addition to the tonic correlation that has been demonstrated previously. Both types of basal forebrain neurons change their firing rate prior to the change in cortical EEG, suggesting that the basal forebrain neurons may have a regulatory influence on the EEG. © 1997 Elsevier Science B.V. All rights reserved.

Parvalbumin-containing neurons in the basal forebrain receive direct input from the substantia nigra-ventral tegmental area

By means of anterograde tracing of Phaseolus vulgaris-leucoagglutinin (PHA-L) it was determined if parvalbumin-immunoreactive neurons in the basal forebrain receive a direct synaptic input from the A9–A10 dopaminergic nuclei of the substantia nigra and ventral tegmental area. Forebrain sections were processed for immunocytochemical detection of PHA-L and parvalbumin (PV) at light and electron microscopic levels. At the ultrastructural level, PHA-L-labeled terminals were found to establish synaptic contacts with PV-immunoreactive neuronal somata in the ventromedial globus pallidus, the ventral pallidum, the internal capsule, and the substantia innominata. PV-containing neurons in pallidal and adjacent basal forebrain territories are thus directly targeted by presumably A9–A10 dopaminergic neurons and represent a novel aspect of midbrain dopaminergic control of basal forebrain neuronal activity.

Sleep-related neuronal discharge in the basal forebrain of cats

Although evidence suggests that the basal forebrain contains a hypnogenic mechanism, putative sleep-promoting neural elements within this area have not been identified. We examined basal forebrain neuronal activity during waking, non-rapid-eye-movement (NREM) sleep, REM sleep and various transition states. Based on state-related discharge rates, 3 cell types were defined. Thirty-nine of 83 cells were classified as waking-active, i.e. waking discharge rates were 2 times NREM sleep rates. Twenty-three of 82 cells were classified as state-indifferent (waking and NREM rates differed by a factor of < 2). NREM sleep discharge rates of the remaining 20 cells were > 2 times waking rates. These were labeled sleep-active cells. Discharge rates of these cells during epochs of alert waking were low, averaging < 1 spike/s. Maximal discharge rates occured during NREM sleep, averaging 9.44 spike/s. Increased discharge of sleep-active cells anticipated sleep onset; cells had an average discharge rate of 6.60 spike/s during transitions between waking and NREM sleep. Sleep-active cells were confined to the ventral basal forebrain, in the horizontal limb of the diagonal bands of Broca, substantia innominata, entopeduncular nucleus and ventral globus pallidus. These areas overlap, in part, with those where chemical, thermal and electrical stimulations evoke sleep, and where lesions suppress sleep. Based on location and discharge pattern, we consider sleep-active cells candidates for mediating some of the sleep-promoting functions of the basal forebrain.

Activity of basal forebrain neurons in the rat during motivated behaviors

The activity of single neurons in the basal forebrain was recorded in the freely-moving rat with moveable fine-wire electrodes. Neural activity was observed while the water-deprived male rat was exposed to three different types of motivating stimuli that elicit locomotion in a running wheel: an estrous female rat; a drinking tube containing water; and grasping and lifting by the experimenter. The neural activity was also observed when the subject was presented with standardized sensory tests and during single pulse stimulation of other brain structures. A majority of the 76 neurons recorded in the forebrain changed their firing rate during orienting and/or locomotion in general (23 neurons) or during behavior related to only one of the specific motivational contexts: the conspecific female (4 neurons); water (7 neurons); or grasp by the experimenter (8 neurons). Whereas the neurons related to orienting and/or locomotion in general were scattered through various brain structures, those neurons related to specific motivational contexts were concentrated in specific areas: the sexually dimorphic nucleus of the medial preoptic area (conspecific female); lateral septum (water); and lateral preoptic area (water and grasp). The present results, although based on relatively few neurons, are consonant with results of research using other techniques. This indicates that analyses at the level of the single neuron promise to be useful for understanding the role of the basal forebrain in motivational systems.