5-HT₂ receptor involvement in conditioned olfactory learning in the neonate rat pup.

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107

Early olfactory preference learning in rat pups occurs when novel odors are paired with tactile stimulation, for example stroking. cAMP-triggered phosphorylation of cAMP response element binding protein (pCREB) has been implicated as a mediator of learning and memory changes in various animals (Frank and Greenberg 1994). In the present study we investigate whether CREB is phosphorylated in response to conditioned olfactory training as might be predicted given the proposed role of the phosphorylated protein in learning.On postnatal day 6, pups were trained for 10 min using a standard conditioned olfactory learning paradigm in which a conditioned stimulus, Odor, was either used alone or paired with an unconditioned stimulus, Stroking (using a fine brush to stroke the pup). In some instances stroking only was used. The pups were sacrificed at 0, 10, 30, or 60 min after the training. Using Western blot analysis, we observed that the majority of olfactory bulbs in conditioned pups (Odor + Stroking) had a greater increase in pCREB activation at 10 min after training than pups given nonlearning training (Odor only or Stroking only). The phosphorylated protein levels were low at 0 min and at 60 min after training. This is in keeping with the slightly delayed and short-lived activation period for this protein.The localization of pCREB increases within the olfactory bulb as seen by immunocytochemistry. Naive pups were not exposed to odor or training. There was a significantly higher level of label in mitral cell nuclei within the dorsolateral quadrant of the bulb of pups undergoing odor-stroke pairing. No significant differences were observed among nonlearning groups (Naive, Odor only, or Stroking only) or among any training groups in the granule or periglomerular cells of the dorsolateral region. The localized changes in the nuclear protein are consistent with studies showing localized changes in the bulb in response to a learned familiar odor. The present study demonstrates that selective increases in pCREB occur as an early step following pairing procedures that normally lead to the development of long-term olfactory memories in rat pups. These results support the hypothesized link between pCREB and memory formation.

Section: Discussionmentioning

confidence: 99%

Section: Conditioning Experiments and Sacrificementioning

confidence: 99%

pCREB in the Neonate Rat Olfactory Bulb Is Selectively and Transiently Increased by Odor Preference–Conditioned Training

McLean¹,

Harley²,

Darby‐King³

et al. 1999

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107

“…While the present study builds on earlier evidence for intrabulbar effectiveness of a ␤-adrenoceptor agonist (Sullivan et al 2000) and antagonist (Sullivan et al 1992) and on intrabulbar 5-HT depletion (McLean et al 1993(McLean et al , 1996 to argue that the critical necessary and sufficient learning targets are intrabulbar, this is not examined directly here. Each of the drugs used would also have effects at other sites and on other receptors, e.g., clonidine (Eglen et al 1998), phenylephrine (Ishac et al 1987;Gadek-Michalska et al 1990;Watkins et al 1990;Quigley et al 2005), and salbutamol (Waldmeier 1981;Murugaiah and O'Donnell 1995;Garnier et al 1997).…”

Section: Adrenoceptors In Early Olfactory Learningmentioning

confidence: 99%

β1-Adrenoceptor or α1-adrenoceptor activation initiates early odor preference learning in rat pups: Support for the mitral cell/cAMP model of odor preference learning

Harley¹,

Darby‐King²,

McCann³

et al. 2006

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We proposed that mitral cell ␤1-adrenoceptor activation mediates rat pup odor preference learning. Here we evaluate ␤1-, ␤2-, ␣1-, and ␣2-adrenoceptor agonists in such learning. The ␤1-adrenoceptor agonist, dobutamine, and the ␣1-adrenoceptor agonist, phenylephrine, induced learning, and both exhibited an inverted U-curve dose-response relationship to odor preference learning. Phenylephrine-induced learning occurred in the presence of propranolol to prevent indirect activation of ␤-adrenoceptors. ␣1-Adrenoceptor mediation may represent a novel mechanism inducing learning or may increase cAMP in mitral cells via indirect activation of GABA B receptors. Neither the ␤2-adrenoceptor agonist, salbutamol, nor the ␣2-adrenoceptor agonist, clonidine, induced learning.Since initial ground breaking studies in Aplysia (for a review, see Pittenger and Kandel 2003) and later Drosophila (Yin and Tully 1996), there has been interest in the hypothesis that the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate response element binding protein (cAMP/PKA/ CREB) cascade might be a universal mechanism underlying learning and memory. In mammalian models there is also supporting evidence for such an assertion, but in adult rat models the associative pathways involved in recruiting cAMP activation in learning are difficult to identify (Alberini 1999). The rat pup odor preference learning model offers an advantage in that respect as the role of ␤-adrenoceptor activation as an unconditioned stimulus is well established (Sullivan et al. 1989(Sullivan et al. , 1991aSullivan and Wilson 1991;Langdon et al. 1997), and more recently, a causal role for cAMP in this form of associative learning has been demonstrated .In 2003, we proposed that early odor preference learning in the week-old rat pup induced by pairing a novel odor with tactile stimulation (stroking), or with injection of the nonselective ␤-agonist isoproterenol, was mediated by the activation of ␤1-adrenoceptors on mitral cells that interacted with glutamatergic odor input to the same cells (Yuan et al. 2003b). This interaction was proposed to produce alterations in mitral cell connectivity that altered the pup's memory of, and preference for, the novel odor. We showed that ␤1-adrenoceptors are predominantly localized on mitral cells and that they are colocalized there with 5-HT 2A receptors (Yuan et al. 2003b), which facilitate learning by potentiating the cAMP response initiated by ␤1-adrenoceptors. We have also found that cAMP has a causal role in odor preference learning consistent with our hypothesis (Yuan et al. 2003a,b).All previous work with odor preference learning and ␤-adrenoceptor activation has used the nonselective ␤-adrenoceptor agonist isoproterenol. It has not been demonstrated that selective ␤1-adrenoceptor activation produces learning. Isoproterenol, infused directly into the olfactory bulb (Sullivan et al. 2000) or given systemically (Sullivan et al. 1991a;Langdon et al. 1997), induces odor preference learning when paired with a nov...

“…See McLean et al (1996) for the procedure in detail. The percentage of time each pup spent on peppermint-scented bedding over five testing trials was calculated.…”

Section: Natural Learningmentioning

confidence: 99%

A temporal-specific and transient cAMP increase characterizes odorant classical conditioning

Cui

Smith²,

Darby‐King³

et al. 2007

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Increases in cyclic adenosine monophosphate (cAMP) are proposed to initiate learning in a wide variety of species. Here, we measure changes in cAMP in the olfactory bulb prior to, during, and following a classically conditioned odor preference trial in rat pups. Measurements were taken up to the point of maximal CREB phosphorylation in olfactory bulb mitral cells. Using both drug and natural unconditioned stimuli we found effective learning was associated with an increase in cAMP at the end of the conditioning trial, followed by a decrease 5 min later. This early timing of a transient cAMP increase occurred only when the odor was paired with an effective drug or natural unconditioned stimulus (US). The data support the hypothesis that the rate of adenylate cyclase activation is enhanced by pairing calcium and G-protein activation and that the timing of transient cAMP signaling is critical to the initiation of classical conditioning.