Overview [ + ][ - ]

Neuromodulatory transmitters influence most neuronal processes including sensory gating, sleep-wake cycle and learning, while their dysregulation underlies a range of neuropsychiatric disorders including depression and anxiety. My long-term research goal is to understand how neuromodulatory transmitters such as noradrenaline and acetylcholine regulate neuronal activity in the brain.

To learn how neuromodulators influence sensory processing and behavior our lab uses olfaction as a model system Currently, our research focus is on the olfactory bulb (OB), the gateway of odor information into the brain, and the first area where odor processing occurs. Specifically, we use targeted expression of optogenetic and chemogenetic tools to precisely control the activity of neuromodulatory neurons that regulate the OB circuit, and learn how this regulation influences odor-guided behaviors.

Exceptionally, the OB is among the few neural circuits known to incorporate adult-born neurons in the brain. Thus, another research area in our lab addresses how neuromodulation and odor-guided behaviors drive the integration of inhibitory neurons into preexisting circuits of the adult brain. Our research advances the understanding of sensory and cognitive functions while providing fundamental translational information for the development of therapeutic strategies that combat brain disorders.

In addition to research, a rewarding aspect of academic life is the teaching and training of young scientists. In the past years, I had the privilege of mentoring a number of bright and promising minds, including 35 undergraduate, 6 graduate and 5 high school students. Please visit the Lab News page to learn about their achievements and current positions.

Neuromodulation in the Olfactory Bulb [ + ][ - ]

The olfactory bulb (OB) is the first area of the brain where processing of odor information occurs. The OB consists of two regions, the main olfactory bulb (MOB), which receives information about general odors such as those associated with food and environment and is part of the main olfactory system. The accessory olfactory bulb (AOB), which is part of the Vomeronasal system, is located in the posterior region of the bulb and receives information about odors important for social interactions such as mating and aggression, semiochemicals usually known as pheromones. In both regions, axons of sensory cells synapse onto the dendrites of second order projection neurons known as mitral and tufted cells (MC).

An important aspect of odor processing relies on the activation of inhibitory neurons in the OB. Two main classes of interneurons, the granule and periglomerular cells (GC and PG), form widespread synaptic interactions with MC. Dendrodendritic synapses between MC and GC consist of an excitatory glutamatergic input from MC to GC, which activates the release of GABA from the dendrites of GC, which in turn inhibits MC. These synapses have been investigated thoroughly and are thought to contribute to several olfactory computations by the OB including gain control and spatial decorrelation.

The activity of MC is highly influenced via top-down regulation by excitatory feedback projections from the piriform cortex. In addition, several neuromodulatory projections, including the noradrenergic and cholinergic systems, play important roles in shaping synaptic fucntion in the OB; a potential target of these modulatory actions is the inhibitory output of GC at dendrodendritic synapses. Following are some of the contributions our lab has made in these areas.

Cholinergic System [ + ][ - ]

In the olfactory system acetylcholine (ACh) facilitates the perceptual learning of odors. The main cholinerigic projections to olfactory areas, including the OB, arises from a cluster of neurons residing in the basal forebrain (the HDB). Our lab has recently shown that despite the presence of a conserved neural circuit in the MOB and AOB, muscarinic ACh receptor activation exhibits marked differences in modulation of neurons in these regions. Muscarinic receptor activation by oxotremorine (oxo) excites AOB principal neurons while MOB neurons are inhibited. We also find that GC exhibit a complex response to muscarinic activation. While in the AOB GC are excited, in the MOB muscarinic receptor activation inhibits GC but it also produces an increase in excitability in response to cell depolarization.

To examine the role of cholinergic modulation in the Vomeronasal system we are using a chemogentic approach that relies on virus-mediated targeted expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to stimulate (hM3Dq) or inhibit (hM4Di) the activity of cholinergic neurons in the HDB. In freely behaving mice, injection of CNO, the exogenous ligand that activates the hM4Di DREADD, supressed the aversion of the intruder to the odor of the resident post fight in the resident-intruder paradigm.

Noradrenergic System [ + ][ - ]

Release of noradrenaline (NA) in the OB is thought to have a permisive role during social behaviors that relie on olfaction. For example, during mating, female mice learn the odor of the stud and this is dependent on NA increased levels in the AOB. Similarly, an increases in NA in the MOB during parturation allows ewes to quickly recognize the odor of their newborn. However, the cellular targets or the specific synaptic changes that underlie these circuit-level responses to NA in the OB are not well understood. Our lab has shown that a major effect of NA in the OB is to enhance the activity of GC, which in turn increases the inhibitory tone onto MCs. This increase in excitabilty in response to NA also includes the apperence of a slow afterdepolarization following a stimulus-induced train of action potentials, which promotes persistent firing. In other studies we have shown that activation of M1 ACh receptors and class I metabotropic glutamate receptors aslo enhance excitabilty in GC by a similar mechanism.

Intrinsic and Extrinsic Inhibiton in the OB [ + ][ - ]

In the OB, the ratio of inhibitory to excitatory neurons is one of the highest compared to other cortical regions highlighting the important role of inhibition in olfactory computatons by the OB. Extensive work has examined the excitatory cortical feedback onto GC and the role of this regulation in shpaing MC firing. In addition our work has shown that top-down regulation by NA and ACh increases the excitability of GC. What mechanisms exixt to balance this excitatory drive? Using single-photon uncaging of GABA we have shown prominent inhibitory responses throughout the GC neuroaxis in MOB and AOB. More recently, using an optogenetic and chemogenetic approach we have provided direct evidence that GC in the OB are regulated by GABAergic neurons from the HDB and that disrupting this inhibition affects odor discrimination. We propose this inhibition, like the excitatory feedback, contribute to fast changes in olfactory coding in the OB in response to rapid changes in environmental context.

Adult Neurogenesis of Inhibitory Neurons [ + ][ - ]

Adult neurogenesis and the integration of newborn inhibitory neurons into mature circuits provides an attractive plasticity mechanism for learning associated to olfactory mediated behaviors. As these newborn neurons integrate in already existing functional circuits, their integration is thought to be highly regulated. Using a marker of dividing cells, BrdU, to label newborn neurons, we have provided evidence that adult neurogenesis is sex and age dependent. Both male and females show a decline in adult neurogenesis in both the MOB and the AOB, howevre only in the AOB we obesrved a and can be affected by sensory stimuli. Moreover, these stimuli can differentially regulate adult neurogenesis in the anterior-posterior regions of the AOB. These subregions of the AOB are thought to process stimuli of different quality. We are currently studiyng mechanisms that ensure the survival of these newborn cells and their stabilization into existing neuronal networks.

Current Funding [ + ][ - ]

  • Our research is funded by an NIA R01-AG049937 (4/15/2015-1/31/2020) grant to R.C.A. (Co-PI)
  • Ruilong Hu is s recipient of an NSF fellowship.

Previous Funding [ + ][ - ]

  • NIDCD R01-DC-009817 (12/1/2009-11/30/2014) grant to R.C.A. (PI)
  • Alexia Nunez-Parra was recipient of a fellowship from the Chilean government (Becas Chile).
  • Richard Smith was a recipient of an NSF fellowship and a Chateaubriand fellowship from the French government