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Noradrenergic projections and receptors in V1

Noradrenaline (NA) cortical afferents are derived primarily from the locus coeruleus (LC) (Freedman et al., 1975; Foote et al., 1983). Tract-tracing studies have demonstrated that the NA projections from LC to the visual cortex are robust and bilateral across a number of species (Gatter and Powell, 1977; Dursteler et al., 1979; Tigges et al., 1982; Sato et al., 1989).

NA synthesis is catalyzed by the enzyme dopamine-beta-hydroxylase (DBH), using dopamine as a precursor; this enzyme therefore can serve as a cytochemical marker for the presence of NA in axons and cell bodies. Axons containing this enzyme are found in all cortical layers. Unlike other types of afferents that enter specific cortical regions radially, NA-containing axons innervate all six cortical layers in an unusual way. Fibers that have reached the rostral cortical poles extend caudally, innervating longitudinal slabs of cortex from the frontal to occipital pole (Morrison et al., 1981).

The density of DBH-immunoreactive fibers differs by cortical area and layer, depending on the species studied (Kosofsky et al., 1984; Gu, 2002). There are highly differentiated laminar orderings of NA throughout the cortex, including V1 (Gatter and Powell, 1977; Dursteler et al., 1979; Tigges et al., 1982; Kosofsky et al., 1984). Descriptions of intracortical NA fiber trajectories and distributions obtained from the rat only weakly predict what is found in the primate cortex (Foote et al., 1983) and NA innervations of the primate cortex have a far greater regional variation in density and pattern relative to that of the rat.

In the rat, DBH-immunoreactive fibers are dense in the superficial layers (Morrison et al., 1978). To the contrary, in the cat V1, fibers are abundant in both supragranular and infragranular layers, with a low density of DBH-pos-itive inputs observed in the thalamorecipient layer IV (Liu and Cynader, 1994). NA fiber innervation of V1 in New World Guyanan squirrel monkeys (Saimiri sciureus) is most dense in infragranular layers, moderate in supra-granular layers, and virtually absent in layer IV (Morrison et al., 1982b; Morrison et al., 1982a). Squirrel monkeys have a laminar distribution of NA innervation in V1 that is dissimilar from that found in the Old World cynomolgus monkey (Macaca fascicularis) (Foote and Morrison, 1984). In the V1 of adult cynomolgus monkeys, noradrenergic fibers are sparse relative to those of other neurotransmitters systems such as the serotonergic system (details below), and laminar differences in NA axon density are not detectable (Kosofsky et al., 1984). NA axons in the cynomolgus monkey form two broad bands of moderate density throughout deep and superficial layers, and intermediate layer IVc shows very few NA fibers (Kosofsky et al., 1984).

NA innervation has also been mapped via DBH-immunoreactivity in the human visual cortex (Gaspar et al., 1989). In humans, NA axons are present in all cortical layers. DBH-immunoreactive fibers are most dense in layer V, followed by VI, and NA innervations are sparse in all other cortical layers.

Adrenoreceptors are coupled to G proteins; activation of these receptors therefore influences a number of second messengers systems. Adrenoreceptors are pharmacologically differentiated into the alpha and beta receptor families, each of these families being further subdivided into a number of subtypes, based upon the results of pharmacological and cloning studies (for reviews see Hoffman and Lefkowitz, 1980; Jonowsky and Sulser, 1987; Civantos Calzada and Aleixandre de Artinano, 2001). The beta receptors are differentiated from alpha receptors by their sensitivity to isoproterenol. All three of the beta receptor subtypes (beta1, beta2, and beta3) facilitate synthesis of cAMP, but only beta1 and beta2 are found in the cortex (for review see Stiles et al., 1984).

The beta1 and beta2 subtypes are linked to a stimulatory G protein that leads to enhanced catalytic activity of adenylyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The alpha1 and alpha2 subtypes are also found in the cerebral cortex. Activation of alpha1 receptors stimulates the phospholi-pase C pathway, leading to mobilization of intracellular Ca2+ via increased levels of the second messengers IP3 and DAG; activation of alpha2 receptors inhibits adenylyl cyclase through an inhibitory G protein, reducing intracel-lular cAMP levels (Berridge, 1998).

Primary visual cortex has a similar laminar distribution of alpha1, beta1, and beta2 subunits with high densities of receptors in superficial layers, low densities in the middle layers and intermediate densities in the infragranular layers. This overall distribution pattern is seen in the cat (Aoki et al., 1986; Parkinson et al., 1988a; Jia et al., 1994), the New World common marmoset (Callithrix jacchus) (Gebhard et al., 1993), and the Old World rhesus monkey (Macaca mulatta) (Bigham and Lidow, 1995). The alpha2 receptor shows a different distribution: in cats alpha2 receptor density is lowest in layer VI (Jia et al., 1994), and in one study this receptor was only observed in a single band occupying layers II and III (Parkinson et al., 1988a). The laminar distribution pattern of NA fibers in the cat visual cortex resembles that of beta-adrenergic receptors, and differs from the distribution pattern of alpha-adrenergic receptors (Liu and Cynader, 1994), suggesting that beta-receptors are anatomically well positioned to participate in key functional roles in V1 (discussed below). In rhesus monkeys, alpha2 receptor densities are highest in layers III, IVa, IVc, and VI (Bigham and Lidow, 1995).

Noradrenergic effects on physiological properties of V1 neurons and plasticity

Earlier reports that characterized the contributions of NA to the modulation of response properties within sensory cortices used a number of strategies.

They have included the local delivery of NA into sites of interest via iontophoresis, electric stimulation of the noradrenergic locus coeruleus (LC) and pharmacological intervention directed at specific noradrenergic receptors.

Noradrenaline has been shown to markedly affect neuronal properties within V1 of both adult and juvenile animals; age differences do not appear to influence noradrenergic modulation on visual cortical neurons (Kasamatsu and Heggelund, 1982; Videen et al., 1984; Ego-Stengel et al., 2002).

For example, pharmacological antagonism of both alpha and beta receptors are known to alter spontaneous response properties of cat V1 neurons, suggesting that endogenous NA contributes to regulating normal cell activity (Sato et al., 1989). NA effects on cortical neurons, however, appear to be expressed in a bi-directional fashion, promoting both excitation and inhibition (Videen et al., 1984; Sato et al., 1989). For example, Sato and colleagues (1989) have shown that electrical stimulation of the LC suppressed V1 neuronal activity in about half of the cells recorded in their experiments. Other cells exhibited a facilitation of activity under conditions of enhanced noradrener-gic tone. Interestingly, the nature of this differential effect of NA on V1 activity appears to be related to cortical layer, where facilitation was observed in neurons within the granular and supragranular layers, while depressive effects appeared to prevail in the infragranular layers (Sato et al., 1989). It has been proposed that this disparity in the neuronal response under enhanced NA reflects different patterns of LC projections across layers of V1 (Sato et al., 1989). Differential distribution of NA receptors across cortical layers could also account for these seemingly opposite effects of noradrenergic input. This hypothesis is supported by findings where antagonism of beta receptors affected response suppression, while alpha-specific antagonism interfered with the facilitatory effects triggered by enhanced levels of NA (Sato et al., 1989). Recent experiments conducted in a slice preparation have provided evidence for a role for NA in suppressing horizontal propagation of activity in rat V1 by decreasing excitatory and increasing inhibitory transmission directed at supragranular pyramidal neurons (Kobayashi et al., 2000). Studies conducted in the rat (Kolta et al., 1987; Waterhouse et al., 1990) and cat (Kasamatsu and Heggelund, 1982) visual cortex also suggested that NA acts to either modulate depression of baseline activity or to enhance visually-driven responses. For example, it has been reported that iontophoretic application of NA within rat V1 unmasked visually-driven responses originally suppressed prior to NA application. In these experiments, the authors also observed that local NA application enhanced RF border contrast (Waterhouse et al., 1990).

It also appears that more complex visual cortex network properties are modulated by noradrenergic input, although the reported findings have been contradictory. For example, it has been reported that local iontophoretic application of NA in V1 increases the selectivity of neurons for direction and speed of moving visual stimuli (McLean and Waterhouse, 1994), while other research groups have reported effects for NA on both orientation and direc tional selectivity (Madar et al., 1983). Experiments performed in adult rats, where pharmacological depletion of LC was conducted, also provided evidence for a role of NA in regulating V1 neuronal properties. These results show that orientation selectivity is severely impaired by decreased noradrenergic input. In addition, it was reported that receptive-field areas were expanded under these conditions, while the signal-to-noise ratio of neuronal responses appear to decrease (Siciliano et al., 1999). To the best of our knowledge there is no report to date that reconciles such discrepant results, possibly indicating that arousal and/or attentional levels might directly impact sensory processing at the level of V1. In fact, it has been shown that enhancement of noradrenergic LC activity contributes to attentional shifts in the rat during visual discrimination tasks (Devauges and Sara, 1990) and other learning paradigms (Carli et al., 1983; Everitt et al., 1983; Pisa et al., 1988; Selden et al., 1990b; Selden et al., 1990a). Currently we are not certain whether such effects of altered LC neuronal firing associated with behavioral states translates into differential NA modulation of visual cortical cells, a hypothesis that remains to be investigated.

Roles for noradrenergic inputs have also been demonstrated during ocular dominance (OD) plasticity. Pioneering experiments primarily conducted by Kasamatsu and colleagues have investigated the effects of eyelid suture coupled with intraventricular 6-OHDA treatment, a common chemical methodology used to deplete forebrain catecholaminergic transmission (Kasamatsu and Pettigrew, 1979). In these experiments, it was observed that animals treated with 6-OHDA exhibited an elevated percentage of cells with binocular responses, whereas control kittens, which underwent eyelid suture in the absence of 6-OHDA intervention, exhibited marked proportions of monocularly-driven neurons (Kasamatsu and Pettigrew, 1979). These experiments have suggested that catecholamines are major participants in the induction and/or maintenance of plastic states within the kitten V1. Direct evidence for the participation of NA in this process was obtained by the same group, where the same experiments were performed as outlined above, but in conjunction with local V1 NA infusion (Kasamatsu et al., 1979). As observed in their previous experiment (Kasamatsu and Pettigrew, 1979), 6-OHDA prevented OD shifts triggered by monocular deprivation. However, when NA was infused locally in combination with 6-OHDA treatment, plasticity was restored within V1, providing direct evidence for the participation of NA in maintaining V1 in a plastic state. Subsequent experiments have revealed that at least part of this effect was mediated through beta receptors in a concentration-dependent fashion (Kasamatsu and Shirokawa, 1985; Shirokawa and Kasamatsu, 1986). These data are in accordance with recent experiments that showed that monocular deprivation leads to an increase in beta1-receptor, but not alpha1-receptor, immunoreactivity in the visual cortex ipsilateral to the deprived eye in kittens (Nakadate et al., 2001). Interestingly, experiments conducted in the adult cat, where OD shifts do not occur (Hubel and Wiesel, 1970), using NA infusion or LC stimulation coupled with monocular deprivation, showed a significantly decreased number of binocularly-driven V1 neurons (Kasamatsu et al., 1979; Kasamatsu et al., 1985).

Noradrenaline and the control of plasticity-regulated gene expression

Beta receptor activation via NA binding leads to stimulatory G-protein (Gs) activation which, in turn, enhances catalytic activity of adenylyl cyclase (AC). AC catalyzes the conversion of ATP into cAMP, and increased cyto-plasmic cAMP levels activate cAMP-dependent protein kinase A (PKA). The PKA pathway has been repeatedly implicated in a number of cellular plasticity mechanisms, including OD plasticity, and has been shown to involve the regulation of ERK/MAP Kinase regulation and CREB phos-phorylation pathways (see Chapter 8). For example, it has been demonstrated that local pharmacological intervention that mimics enhanced strength of the PKA contributes to the restoration of OD plasticity in adult cats (Imamura et al., 1999). These results suggest that cAMP-sensitive pathways are involved in the maintenance of plasticity in V1. A critical question that arises from these experiments is whether these biochemical cascades involved in V1 plasticity trigger a gene expression program that is involved in regulating activity-dependent changes in the visual cortex. If so, it is important to define what genes participate in the neural plastic response. We have explored this possibility by focusing our own investigations on an activity-dependent, candidate-plasticity gene, the nerve-growth factor induced gene-A (NGFI-A). NGFI-A has been the focus of extensive study for the past few years as it is well positioned to orchestrate waves of gene expression involved ultimately in structural and functional rewiring of central nervous system (CNS) networks (reviewed in Knapska and Kaczmarek, 2004; Pinaud, 2004) (see also Chapter 8). NGFI-A encodes a transcrip-tional regulator that is sensitive to neuronal depolarization and has high affinity for a specific DNA motif found in the promoter region of a large number of genes expressed in the CNS (Milbrandt, 1987; Christy and Nathans, 1989). It has been shown that NGFI-A plays a role in the regulation of a number of genes that are putatively involved in CNS plasticity. For example, NGFI-A regulates the expression of the synapsin I and synapsin II genes, in addition to the gene that encodes synaptobrevin II (Thiel et al., 1994; Petersohn et al., 1995; Petersohn and Thiel, 1996). These genes have been shown to regulate the size of the readily releasable pool of neurotransmitter vesicles, and transmitter release (Hilfiker et al., 1999). NGFI-A has also been involved in the putative regulation of the monoamine oxidase B gene, neurofilament, the adenosine 5'-triphosphate binding cassette, sub-family A, transporter 2 (ABCA2) and the alpha-7 subunit of the nicotinic acetylcholine receptor (Pospelov et al., 1994; Carrasco-Serrano et al., 2000; Wong et al., 2002; Davis et al., 2003; Mello et al., 2004), thus likely to directly impact neuronal cell physiology, from neurotransmitter release and membrane transport to the regulation of cell excitability and neurotransmitter degradation rates. NGFI-A expression has been repeatedly correlated with classic plasticity inducing paradigms such as exposure to enriched visual environments (Wallace et al., 1995; Pinaud et al., 2002; Pinaud, 2004), which have been demonstrated to trigger widespread structural modifications in V1 connectivity (Volkmar and Greenough, 1972). In addition, NGFI-A expression is dependent on the activation of the NMDA-type glutamatergic receptors, which have been repeatedly implicated in various forms of enhanced synaptic efficacy, such as long-term potentiation (Cole et al., 1989; Wisden et al., 1990). Finally, NGFI-A expression is dramatically down-regulated in response to dark-adaptation and induced strongly by subsequent light-stimulation, another paradigm associated with visual system plasticity (reviewed in Kaczmarek and Chaudhuri, 1997; Herdegen and Leah, 1998; and Pinaud et al., 2000; Pinaud et al., 2003). We used the latter paradigm to investigate the contributions of noradrenergic input to the regulation of NGFI-A in the adult rat visual cortex (Pinaud et al., 2000). In our control experiments we found that dark adaptation significantly decreased the number of NGFI-A positive cells in the rodent V1, while a brief subsequent visual experience (light exposure) triggered a marked increase in NGFI-A expression across all cortical layers, with the exception of layer I, a finding that is in accordance with previously published results (Kaczmarek and Chaudhuri, 1997; Herdegen and Leah, 1998; Pinaud et al., 2000). We next ablated noradrenergic projections to V1 by locally infusing 6-OHDA within the LC, conducted the dark adaptation/light stimulation protocol and evaluated the patterns of NGFI-A expression in V1. Interestingly, 6-OHDA treatment prevented light-induced NGFI-A expression, providing direct evidence that noradrenergic input is required for NGFI-A induction (Pinaud et al., 2000). These experiments show, therefore, that NA directly modulates the activation of genetic mechanisms that are sensitive to sensory stimulation and possibly involved in the machinery required for CNS plasticity. Given that NGFI-A expression depends on increased cAMP levels and PKA activation, and NA potentiates this pathway through beta-adrenoreceptors, future work with selective antagonists targeted at each step of this biochemical cascade will allow a more detailed characterization of the second messenger systems involved in the induction of candidate-plasticity genes associated with experience-dependent cortical plasticity. An alternative role for NA in NGFI-A induction could be to regulate appropriate intracellular calcium levels required to trigger gene expression, along with other sources of calcium. NMDA receptor activation leads to calcium influx required for NGFI-A induction, however, a concomitant activation of beta-adrenocep-tors could also potentially mobilize calcium from intracellular stores through a rise in IP3 levels. Should this hypothesis prove to be correct, ablation of noradrenergic projections could significantly reduce intracellular calcium levels to prevent NGFI-A expression from occurring. This hypothesis, however, remains to be tested experimentally.

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