Synapse formation is associated with memory storage in the cerebellum

Abstract

The idea that memory is encoded by means of synaptic growth is not new. However, this idea has been difficult to demonstrate in the mammalian brain because of both the complexity of mammalian behavior and the neural circuitry by which it is supported. Here we examine how eyeblink classical conditioning affects synapse number within the cerebellum; the brain region essential for long-term retention of the conditioned response. Results showed eyeblink-conditioned rats to have significantly more synapses per neuron within the cerebellar interpositus nucleus than both explicitly unpaired and untrained controls. Further analysis showed that the increase was caused by the addition of excitatory rather than inhibitory synapses. Thus, development of the conditioned eyeblink response is associated with a strengthening of inputs from precerebellar nuclei rather than from cerebellar cortex. These results demonstrate that the modifications of specific neural pathways by means of synaptogenesis contributes to formation of a specific memory within the mammalian brain.For every act of memory, every exercise of bodily aptitude, every habit, recollection, train of ideas, there is a specific neural grouping, or co-ordination, of sensations and movement, by virtue of specific growths in cell junctions (1).T he neural circuits critical for the acquisition and performance of the conditioned eyeblink response are localized to the cerebellum (2). Information regarding the unconditioned stimulus (US) and conditioned stimulus (CS) converge within both the cerebellar cortex and the interpositus nucleus. CS information is relayed via ponto-cerebellar projections, whereas US information is relayed via the olivo-cerebellar pathway (2, 3). Although the cerebellar cortex is involved in modulating some aspects of the conditioned response (CR) (4, 5), the interpositus nucleus is the critical brain structure supporting long-term retention of the CR (2, 6, 7). Neuronal activity within the interpositus nucleus is highly correlated with development of the CR (5, 7), and inactivation of the interpositus prevents both CR acquisition and performance (8).Although the locus of the memory trace is clear, the cellular mechanisms underlying the formation of the CS͞US association are poorly understood. Several mechanisms have been proposed, including increases in the intrinsic excitability of interpositus neurons and reduced inhibition via depression of Purkinje cell activity (9). The fact that inhibition of specific synaptic enzymes (10) and neurotransmitter receptors (11) within the interpositus nucleus impair learning suggests that changes in synaptic function are involved. Transient changes in enzyme or receptor activity, however, would seem incapable of supporting the long-term encoding of the CS͞US association. Recent work has shown that microinjections of a protein synthesis inhibitor into the interpositus nucleus impairs the acquisition but not the expression of the CR (12). This finding suggests that strengthening of the CS pathway may involve more...

Learning-Induced Plasticity in Deep Cerebellar Nucleus

“…Our results add to the evidence that in addition to the classical site of plasticity in the cerebellar cortex (Marr, 1969;Albus, 1971), eyelid conditioning induces plasticity in the AIN (Kleim et al, 2002). The existence of an analogous form of plasticity in the vestibular nucleus and the notion that its induction is controlled by inputs from Purkinje cells was first suggested by Miles and Lisberger (1981) for another form of cerebellar motor learning known as vestibulo-ocular reflex (VOR) adaptation, and evidence in support of this view has been obtained in subsequent studies (Lisberger, 1994;du Lac et al, 1995).…”

“…Our results eliminate alternative candidate sites of plasticity that are either upstream or downstream from the AIN, suggesting that SLRs reflect a form of plasticity at the excitatory synapses of mossy fibers onto AIN neurons (Racine et al, 1986;Kleim et al, 2002;Pugh and Raman, 2006;Zhang and Linden, 2006). They provide new support for the view that cerebellar learning in general involves plasticity in the cerebellar cortex and in its downstream target neurons in the deep cerebellar and vestibular nuclei.…”

“…One of two general mechanisms, synaptic plasticity at mossy fiber-to-AIN synapses (Racine et al, 1986;Kleim et al, 2002;Pugh and Raman, 2006;Zhang and Linden, 2006) or a cell-wide increase in the intrinsic excitability of AIN neurons (Aizenman and Linden, 2000;Zhang et al, 2004), could mediate SLRs. To test these alternatives, we examined the stimulus specificity of SLRs established with a mossy fiber stimulation CS (Fig.…”

“…A pairing-specific increase in the number of excitatory synapses in the AIN (Kleim et al, 2002) and/or long-term potentiation (LTP) at the mossy fiber-to-AIN synapse (Racine et al, 1986;Pugh and Raman, 2006) have been reported. Persistent increases in the intrinsic excitability of deep cerebellar nucleus neurons (Aizenman and Linden, 2000;Nelson et al, 2003Nelson et al, , 2005Zhang et al, 2004) could also contribute, but such changes must be region specific (Zhang and Linden, 2003) to explain the stimulus specificity of SLRs (Perrett and Mauk, 1995;Ohyama et al, 2003).…”

“…Additional training induces plasticity in the AIN at mossy fiber synapses coactive with this Purkinje cell pause (Medina and Mauk, 1999;Pugh and Raman, 2006). For instances of learning such as eyelid conditioning in which the CS-activated mossy fiber input has not previously modulated the target response, mossy fiber-to-AIN synapses may not yet exist, and thus their formation (Kleim et al, 2002) may be necessary before they can undergo LTP.…”