Research reportThe effect of prefrontal stimulation on the firing of basal forebrain neurons in urethane anesthetized rat
Introduction
The basal forebrain (BF) is located at the medial and ventral part of the cerebral hemispheres. This area, including the medial septum, diagonal band nuclei, substantia innominata, pallidal (ventral pallidum, globus pallidus), and peripallidal regions, contains a heterogeneous population of neurons regarding their neurotransmitter content, morphology and projection pattern [1], [63], [64], [68]. Among its cell populations, the cholinergic corticopetal projection neurons have received particular attention due to their loss or metabolic down regulation in Alzheimer's and related disorders [2], [20], [27], [40]. Cholinergic neurons in the BF provide the major extrinsic source of acetylcholine (ACh) to the cerebral cortex. Maximal release of ACh occurs in the cortex in association with cortical activation during states of waking and paradoxical sleep, suggesting that this projection is critically involved in the maintenance of cortical activation and in the process of normal wakefulness [12], [44], [48]. Cholinergic neurons are co-distributed with several other cell populations, including various calcium binding protein containing cells (e.g. calbindin, calretinin, parvalbumin), glutamatergic and GABAergic neurons [33], [34], [31], [46], [18], [25]. Tracing studies using electron microscopy have identified synapses on BF neurons originating in the brainstem, hypothalamus, amygdala, substantia nigra-ventral tegmental area, striatum and the prefrontal cortex [63], [18], [6], [19], [69], [66], [65], [70].
Experiments in animals, including primates [5], [49], and human imaging studies [4], [35], [36], [38], [39] suggest the involvement of the prefrontal cortex (PFC) in higher cognitive functions, including planning, working memory and attention. Lesions in the BF, in experimental animals, resulted in attention deficits [58], [60] and pharmacological manipulation in the PFC resulted in altered ACh efflux in posterior cortical areas [48], [43], [42], [50], suggesting that a prefrontal-basalo-cortical circuitry may participate in the modulation of sensory processing.
Considerable amount of evidence has been accumulated on the functional heterogeneity of the PFC in rodents and primates [47]. The PFC is generally defined as that part of the frontal cortex that has reciprocal connection with the mediodorsal thalamic nucleus [16], [55], [57], [59] and receives dense dopaminergic input from the ventral tegmental area [18], [16], [15], [17], [45], [51]. In rodents, the PFC can be partitioned into medial, lateral and ventral or orbital subdivisions. The medial parts comprise the medial precentral area (Prc or M2), the anterior cingulate (Cg), the prelimbic (PL) and infralimbic areas (IL). The ventral areas encompass the medial, ventral, ventrolateral and lateral orbital areas, whereas the lateral subdivisions include the ventral and dorsal agranular insular areas. While the medial precentral and cingulate cortices project only with occasional fibers towards BF areas, the PL, IL and orbitofrontal areas give rise to relatively strong projections that pass through in a medio-lateral topography through BF areas rich in cholinergic neurons [19], [26], [52]. However, according to an electron microscopic study, prefrontal axons terminate exclusively on non-cholinergic neurons, including parvalbumin-containing cells [69].
In previous studies it has been revealed that the majority of BF neurons (so-called F cells) have a strong positive correlation with EEG activity, meaning that cells showed an increased firing rate during low-voltage fast activity (LVFA, f > 16 Hz) in urethane anaesthetized rats. A smaller group of cells (S cells) also showed correlation with the changes in EEG, but in this case there was an increase in the firing rate during slow wave activity (SWA, f < 4 Hz) and they stopped or decreased their firing rate during LVFA [8], [9], [10], [11]. In vivo extracellular recording with subsequent juxtacellular labeling and immunocytochemistry permitted further characterization of BF neurons [31], [13], [32]. Cholinergic neurons correspond to some of the F cells, however, according to our study, PV-containing, putative GABAergic neurons also belonged to the F category [13]. Among the S cells, several neurons containing NPY were found. In an effort to characterize the functional relationship between the PFC and BF areas we were interested to find out what is the functional effect of prefrontal stimulation on BF unit firing. Except one study, that investigated with electrophysiological methods the connection between the dorsomedial part of the PFC (Cg/M2) and BF [23], no data are available how more ventral parts of the PFC affect BF units. In this paper, we investigated the connection between BF and prefrontal areas using stimulation in PL/IL areas and recording single unit activity in the BF during EEG monitoring followed by juxtacellular labeling of the recorded neurons. Also, an attempt was made to immunohistochemically identify the juxtacellularly labeled cells. BF units were categorized in relation to tail-pinch induced EEG changes.
Section snippets
Animal preparation
Experiments were performed on 31 Wistar male rats weighing 250–350 g. Animals were housed in temperature-controlled environment and had free access to food and water. Animals were anesthetized with urethane (1.0–1.2 g/kg, i.p.), plus 4% lidocaine was injected at the cranial incision and ear canals. Supplementary doses of urethane (additional 10% of the original dosage) were also given when slow wave cortical activity appeared to be decreased. Animals showed no behavioral response to tail pinch
Electrophysiology and PFC stimulation
A total of 57 neurons in the BF were studied, whereof 41 (72%) increased discharge rate when LVFA was present in the cortical EEG (F cells) and 9 (15%) showed increased firing rate during SWA. Also we found a group of cells (13%) that showed no correlation with any EEG pattern. We categorized neurons as F or S cells based on their response to tail pinch (TP) stimulation. Units were characterized as F cells if their activity increased due to TP stimulation, in contrast, the activity of S cells
Discussion
The present results confirm previous findings regarding the firing pattern and correlation of BF unit activity to cortical EEG [69], [8], [9], [10], [11]. Activity in the majority of the recorded neurons (50/57) changed in close correlation with cortical EEG. The unit activity of F cells (41/50) was strongly correlated to LVFA while S cells (9/50) remained silent or decreased their firing rate during fast EEG epochs. Stimulation of the medial prefrontal cortex affected 28 F and 8 S cells
Concluding remarks
The electrophysiological diversity of the recorded neurons based on their spontaneous activity and responses to the PFC stimulation reflects the existence of different BF cell types that receive direct or indirect prefrontal input. Unfortunately, we were able to identify only very few neurons chemically, preventing us to establish whether or not the different electrophysiological categories correspond to different cell types or different functional states. The observation, however, in case of
Conflict of interest
None.
Acknowledgements
This research was supported by National Institute of Health grant NS-23945 to L. Zaborszky. The authors thank to Mrs. Jozsef Primas for excellent technical assistance.
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