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.

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.

The understanding of neuronal plasticity in small networks of cultured neurons is key to the development of computers based on neuronal systems. A main goal of this collaborative project is to unravel the simple computational rules underlying learning in functionally connected neuronal networks, and develop trainable networks that selectively respond to spatiotemporal target patterns. To achieve this we use neuronal cultures grown in high density microelectrodes arrays (HD-MEA)(A. figure below). Using this approach, we can record extracellular activity of an entire network of cortical neurons (~200,000), with more than 26,000 electrodes, providing unparalleled spatiotemporal resolution. These neurons are cultured in the presence of astrocytes to improve their fitness and to evaluate the contribution of glia to the development of functional computational networks (B. figure below). We are currently evaluating the ability of these neuronal networks to respond to specific spatiotemporal patterns of electrical and holographic optogenetic stimulation.

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.

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 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.

Our research is funded by the following sources:

• NSF EFRI ELiS 2318027 (09/2023-08/2027) R.C.A. (Co-PI)
• NSF URoL:EN 2133769 (01/2022-12/2026) R.C.A. (Co-PI)
• UMD MPower Seed Grant Challenge (02/2022-02/2024) R.C.A. (Co-PI)
• FONDECYT, Chile (04/2022-04/2025) M. Garcia-Robles (PI), R.C.A., international Co-PI (Money for travel)

• UMD MPower Brain Healthand Human Performance Seed Grant (3/1/2021-6/30/2022) grant to R.C.A.(co-PI)
• NIA R01-AG049937 (4/15/2015-1/30/2021) grant to R.C.A. (co-PI)
• NSF-EAGER: CBET1842315 (9/1/2018-8/31/2019) grant to R.C.A. (co-PI)
• UMD Brain and Behavior Initiative Seed Grant (4/1/2016-4/1/2017) grant to R.C.A. (co-PI)
• ISR-UMD Engineering Systems for Mental Health Seed Grant (2/16/2015-1/16/2016) grant to R.C.A. (co-PI)
• NIDCD R01-DC-009817 (12/1/2009-11/30/2014) grant to R.C.A. (PI)
• NIDCD R03-DC-005559 (5/1/2003-5/1/2006) 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
• Ruilong Hu was a recipient of an NSF fellowship