BioSystems 58 2000 219 – 228
Non-linear cortico – cortical interactions modulated by cholinergic afferences from the rat basal forebrain
Alessandro E.P. Villa
a, ,1
, Igor V. Tetko
a,b
, Pierre Dutoit
a
, Guido Vantini
a
a
Laboratoire de Neuroheuristique, Institut de Physiologie, Uni6ersite´ de Lausanne, Rue du Bugnon
7
, CH-
1005
Lausanne, Switzerland
b
Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kie6, Ukraine
Abstract
In the adult rat most of basal forebrain cholinergic neurons BFCN express the low-affinity p75 nerve growth factor receptor NGFr. The immunotoxin 192 IgG-saporin SAP provokes a selective loss of NGFr-positive BFCN,
somewhat similar to the loss of integrity of BFCN associated with human senile dementia of Alzheimer’s type, whereas NGF exerts a trophic action on BFCN. Cortico – cortical interactions are modulated by cholinergic
projections of BFCN and it is proposed that alterations of these projections by SAP and by NGF produce opposite effects. This hypothesis was tested by recording multiple local field potentials LFPs in the rat temporal cortex and
applying bispectral analysis to measure phase-coupled frequencies, somewhat analogous to frequencies of resonance. Choline acetyltransferase ChAT activity was measured in the septal area in order to assess the effects of the
treatments. NGF-treatment increased ChAT activity by 45 and frequencies of non-linear coupling were shifted towards frequencies higher than 70 Hz, thus suggesting the presence of increased functional interactions in the short
range. By contrast, SAP provoked a decrease of nearly 40 in ChAT activity and an increase of phase-coupling in the low frequencies B 50 Hz, being interpreted as a decreased functional cortico – cortical interaction. Bispectral
analysis revealed features of the effect of BFCN on cortical activity that could not be observed by other means and offers as a valuable tool of study that could be extended to the EEG of Alzheimer’s patients. © 2000 Elsevier Science
Ireland Ltd. All rights reserved.
Keywords
:
Bispectral analysis; 192 IgG-saporin; rhNGF; Alzheimer’s disease cortico – cortical interactions; Temporal cortex; Rat basal forebrain
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1. Introduction
Basal forebrain cholinergic neurons BFCN are distributed throughout the ventral pallidum
and substantia innominata Mesulam et al., 1983. These neurons receive afferences from several ar-
eas, including the midbrain, peripenducular nu- cleus, hypothalamus and amygdala and have a
Corresponding author. Tel.: + 41-21-6925532; fax: + 41- 21-6925505.
E-mail address
:
alessandro.villaiphysiol.unil.ch A.E.P. Villa.
1
http:www.lnh.unil.ch 0303-264700 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 0 3 - 2 6 4 7 0 0 0 0 1 2 6 - X
wide pattern
of projections
to neocortex,
hippocampus, amygdala, olfactory bulbs, thala- mus and brainstem Lamour et al., 1982; Parent
et al., 1988; Chen and Bentivoglio, 1993. Immunohistochemical and in situ hybridization
studies have colocalized on the surface of BFCN Gibbs and Pfaff, 1994 a low affinity neuro-
trophin receptor p75
NGFR
and a high affinity receptor TrkA that bind to nerve growth factor.
Nerve growth factor NGF, Calissano et al., 1984, a member of the neurotrophin family
Thoenen, 1991, is known to exert a trophic action on BFCN Honegger and Lenoir, 1982. In
the adult rat NGF is expressed in specific areas of the forebrain that overlap to a large extent the
regions innervated by BFCN Korsching et al., 1985. It has been shown that in brain regions
innervated by BFCN, the intracerebroventricular ICV administration of NGF induces a dose-de-
pendent, long-lasting increase of the synthetic en- zyme choline acetyltransferase ChAT activity
Fusco et al., 1990 and an enhancement of high- affinity choline uptake, acetylcholine ACh syn-
thesis and release Rylett et al., 1993. Therefore, a prominent and specific activation of BFCN
transmission in vivo is likely to be one of the main mechanisms underlying the effects induced by
NGF in the adult brain.
Experimental studies indicate that BFCN may be involved in the control of shifting attention to
potentially relevant sensory stimuli that predict an event of importance for the individual Chiba et
al., 1995. Interestingly, a hallmark of Alzheimer’s Disease AD is a decrease in number and func-
tion of BFCN Davies and Maloney, 1976. Hu- man patients affected by AD are characterized by
complex cognitive deficiences including impaired ability to shift visuospatial attention Terry and
Katzman, 1983; Scinto et al., 1994. In other mammalian species disruption of several cognitive
functions has also been associated with loss of integrity of BFCN functions Whishaw et al.,
1985. In addition to these findings recent studies about pathological amyloid metabolism associ-
ated to AD Growdon, 1997; Lin et al., 1999 sustain the hypothesis that changes of the cholin-
ergic system associated to primary dysfunction of BFCN might be a main cause responsible of AD
Coyle et al., 1983; Gallagher and Colombo, 1995.
Cholinergic basal forebrain lesions can be used to study the role of the cholinergic system in
cortical arousal and normal cognitive function. The selectivity of these lesions is crucial and has
been achieved using a specific immunotoxin Wi- ley, 1992, which is a monoclonal antibody 192
IgG directed against the low affinity neuro- trophin receptor p75
NGFR
linked to a ribosome- inactivating cytotoxic protein saporin. Injections
of the 192 IgG-saporin SAP provoke selective lesions of NGFR-positive BFCN and decrease of
ChAT activity in widespread areas of the neocor- tex and hippocampus that allow an animal model
to mimic some key features of AD.
In patients affected by AD an increase of slow frequency components and a decrease of low-
voltage fast elect electroencephalographic activity EEG is observed Rae-Grant et al., 1987,
whereas activation of the cholinergic system within the cortex is correlated with higher fre-
quencies Celesia and Jasper, 1966. In rodents, there are evidence that changes in theta rhythm
synchronization are modulated by cholinergic pharmacologically active drugs and by BFCN
Dickson et al., 1994. Entrainment of both tem- poral and frequency domain characteristics of
cortical activity may depend on both cortico – cor- tical connections and divergent thalamocortical
inputs. In either case the extent of frequency and temporal commonality is likely to critically de-
pend on the integrity of BFCN. We recorded multiple local field potentials LFPs in the rat
temporal cortex and investigated the extent of inter-site frequency coupling in the cortex of
NGF-and SAP-treated rats by ICV application of the biologically active compounds. We used bis-
pectral analysis to measure phase-coupled fre- quencies, analogous to frequencies of resonance
Brillinger, 1965; Lii and Helland, 1981; Schanze and Eckhorn, 1997. The hypothesis to be tested
is that SAP-treated animals are characterized by disruption of long cortico – cortical interactions
that correspond to high frequencies of resonance in brain activity. Conversely we expect that NGF-
treated animals are characterized by an extension of the range of cortico – cortical interactions due
to increased BFCN activity, thus giving rise to lower frequencies of resonance.
2. Materials and methods
