Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris‐leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry

Abstract

To verify the possibility that the pedunculopontine nucleus is a source of glutamatergic terminals in contact with midbrain dopaminergic neurons in the squirrel monkey, we used the anterograde transport of Phaseolus vulgaris-leucoagglutinin in combination with preembedding immunohistochemistry for tyrosine hydroxylase and for calbindin D-28k and postembedding immunocytochemistry for glutamate and for gamma-aminobutyric acid. Following tracer injections in the pedunculopontine nucleus, numerous anterogradely labeled fibers emerged from the injection sites to innervate densely the pars compacta of the substantia nigra and ventral tegmental area. The major type of labeled fibers were thin with multiple collaterals and varicosities that established intimate contacts with midbrain dopaminergic neurons. At the electron microscopic level, the anterogradely labeled boutons were medium sized (maximum diameter between 0.9 microns and 2.5 microns) and contained numerous round vesicles and mitochondria. Postembedding immunocytochemistry revealed that 40-60% of anterogradely labeled terminals were enriched in glutamate and formed asymmetric synapses with dendritic shafts of substantia nigra and ventral tegmental area neurons. In triple-immunostained sections, some of the postsynaptic targets to these terminals were found to be dopaminergic. In addition, 30-40% of the anterogradely labeled terminals in both regions displayed immunoreactivity for gamma-aminobutyric acid and, in some cases, formed symmetric synapses with dendritic shafts. In conclusion, our results provide the first ultrastructural evidence for the existence of synaptic contacts between glutamate-enriched terminals from the pedunculopontine nucleus and midbrain dopaminergic neurons in primates. Our results also show that the pedunculopontine nucleus is a potential source of gamma-aminobutyric acid input to this region. These findings suggest that the pedunculopontine nucleus may play an important role in the modulation of the activity of midbrain dopaminergic cells by releasing glutamate or gamma-aminobutyric acid as neurotransmitter.

Reward Prediction Error Computation in the Pedunculopontine Tegmental Nucleus Neurons

“…It is possible that the former and latter fixation target neurons, whose responses were shutdown at the times of the actual and expected rewards, respectively, represent the value functions V(t) and V(t+1) for the current and predicted task events (Houk et al, 1995;Sutton & Barto, 1998;Doya, 2000). Furthermore GABAergic axon terminals originating from the PPTN were observed in the midbrain (Charara et al, 1996), these inhibitory connections may inhibit dopamine neurons and generate the inhibitory reward omission response. Alternatively, the inhibitory reward signals may be sent to the dopamine neurons from other neuronal structures such as the striosome (Brown et al, 1999;Contreras-Vidal & Schultz, 1999), ventral pallidum (Wu et al, 1996), habenula (Matsumoto & Hikosaka, 2007) and rostromedial tegmental nucleus (Jhou et al, 2009).…”

“…substantia nigra pars compacta and ventral tegmental area (Beckstead et al, 1979;Jackson & Crossman, 1983;Beninato & Spencer, 1987;Charara et al, 1996), which encode a reward prediction error signal for reinforcement learning (Schultz, 1998). The PPTN is one of the strongest excitatory input sources for the dopamine neurons (Matsumura, 2005).…”

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

“…prefrontal cortex (56,57), and peduncolopontine tegmental nucleus (58). In turn, endogenous DA can directly influence mDA neurons and their firing via a network feedback mechanism (51,59).…”

Prefrontal Cortical Projections to the Midbrain in Primates: Evidence for a Sparse Connection

“…The main input to the DA cells (either directly or indirectly) is from the striatum. Other sources of regulation of DA are derived from the globus pallidus (GP), the pedunculopontine n. (PPN), and the subthalamic n. (STN) (Carpenter et al, 1981a,b;Parent, 1986;Smith et al, 1990;Rosales et al, 1994;Charara et al, 1996;. Of these inputs, both the striatal and pallidal afferent fibers to the SN are GABAergic.…”