Currently in my lab:
- My laboratory has worked for several years in various projects related to the physiology and pathophysiology of brainstem autonomic neurocircuits, particularly those that regulate gastrointestinal functions. Brainstem autonomic circuits are pathway specific. That is, a neuron’s properties (biophysical, neurochemical, pharmacological) in combination with its synaptic connections to and from other central nuclei define it as belonging to a distinct autonomic pathway. Under this proposal, autonomic circuits are segregated into distinct functional lines and subgroups of neurons are responsible for the integration of homeostatic functions. Autonomic brainstem circuits are not the stereotyped relay networks they have been assumed to be but, instead, are capable of rapid adaptation in response to changing conditions. These adaptations are highly specific in terms of the neuronal populations they target and imply that the visceral parasympathetic output can be tailored to homeostatic requirements in an on-demand fashion. These adaptations may also be triggered inappropriately, however, suggesting that peripheral injury (inflammation, mechanical or chemical insult) or disease (obesity, stress, neurological disorders) may induce longer-term or unwelcome alterations in autonomic brainstem circuits.
Current studies within the lab are investigating:
Vagal neuroplasticity in response to diet as well as the effects of diet on neurocircuit development and the effect this has on adult outcomes
These studies have demonstrated that:
- The homoestatic regulation of energy balance in response to acute high fat diet exposure involves activation of brainstem astrocytes and the recruitment of a complex glutamatergic signaling cascade to delay gastric emptying and regulate food intake to restore caloric balance. The progression of these studies are two-fold: 1) does loss of this glutamatergic signaling cascade contribute to the attenuation of energy homeostasis in the face of continuing exposure to high fat diet, and can re-activation of this signaling cascade restore energy homeostasis and prevent excess caloric intake, and 2) does inappropriate activation of brainstem astrocytes contribute to sickness-induced anorexia, and does blocking this glutamatergic signaling cascade restore appropriate food intake and energy balance
- Maternal exposure to high fat diet during the perinatal period arrests and disrupts the development of autonomic neurocircuits. In particular, perinatal high fat diet exposure decreases descending hypothalamic oxytocin (anti-stress) inputs to the brainstem, and renders corticotropin releasing factor (pro-stress) inputs to the brainstem tonically active, preventing offspring from mounting appropriate stress responses. Future studies will investigate the potential that increased maternal affiliative care upregulates descending oxytocin neurocircuitry, and restores appropriate stress responses. Perinatal high fat diet exposure also dysregulates the normal developmental expression of the potassium chloride cotransporter, KCC2, which is integral to inhibitory GABAergic signaling, in a manner that appears to depend upon postnatal BDNF signaling. Future studies will determine the mechanistic basis for these developmental alterations, and the potential for dietary factors to restore normal development.
Vagal neurocircuit modulation by sex and stress
These studies have demonstrated that:
- In males, the ability to adapt, or develop resilience, to stress and restore appropriate gastrointestinal functions is dependent upon the upregulation of descending hypothalamic oxytocin inputs to the brainstem.
- In females, however, gonadal hormones modulate vagal control of gastrointestinal functions, and dysregulate the ability to develop adaptation (even in a low estrogen state, females resemble “stressed” males)
Future studies will investigate the role of social buffering to mitigate the stress-induced responses on females
The pivotal role of the vagus in neurological disorders, particularly Parkinson’s Disease
Using a novel gut-brain environmental model of parkinsonism in rats, these studies have demonstrated that:
- A monosynaptic connection between the Substantia Nigra pars compacta (SNpc) tonically regulates vagal control of the stomach and colon
- Inhibition of this nigro-vagal neurocircuit prevents the ascending spread of pathological a-synuclein and prevents the loss of SNpc neurons and the development of motor dysfunction
Future studies will investigate if prokinetic drugs and/or increased vagal efferent activity can mitigate the ascending spread of misfolded a-synuclein and the development of maladaptive plasticity. Studies are also ongoing to assess whether the continuing ascending spread of misfolded a-synuclein results in cognitive dysfunction and Lewy body dementia.