The amygdala plays a critical role in the genesis of defensive behaviors. Moreover, it is hyperactive in humans afflicted with anxiety disorders. Thus, it is commonly believed that many anxiety disorders result, at least in part, from a dysregulation of amygdala processes normally mediating fear or defensive behaviors. Accordingly, research on the mechanisms controlling amygdala excitability might open new approaches for the treatment of anxiety disorders. This proposal aims to do just that, by studying the influence of midline thalamic (MTh) nuclei on the amygdala. Prior studies on thalamic influences over the amygdala have focused on inputs arising from the posterior thalamus, particularly from the medial portion of the medial geniculate nucleus. Yet, a number of tracing studies have revealed that MTh nuclei also contribute massive projections to the basolateral (BLA) and central (CeA) amygdala. However, other than anatomical data, little is known about the role of these strong glutamatergic inputs. The work proposed here aims to shed light on the influence of MTh inputs to the amygdala. To this end, we will first identify the targets and postsynaptic mechanisms of MTh inputs in the amygdala using anatomical (Aim #1) and physiological (Aim #2) methods. Indeed, BLA and CeA both contain multiple cell types that express different peptides/receptors and form contrasting connections with each other and extrinsic afferents. Therefore, in Aim #1, we will combine anterograde tracing with immunocytochemistry for various neuronal markers to identify the targets of MTh axon terminals in the amygdala at the light and electron microscopic levels. Building on these results, Aim #2 will combine optogenetic and patch clamp recording techniques in vitro to study the impact of MTh inputs on amygdala cells. Armed with this information, the last two aims will examine the influence of MTh cells on amygdala-dependent functions. Indeed, recent studies have revealed that following muscimol infusions in MTh nuclei, the expression of amygdala-dependent learned and innate fear is drastically reduced. However, it is unclear whether these muscimol findings result from the inhibition of nearby thalamic cells (e.g. mediodorsal nucleus), or the disfacilitaton of other targets of MTh nuclei (e.g. prefrontal cortex), that project to the amygdala. Two differen approaches will be used to address this question. First, in Aim #3, we will perform simultaneous extracellular recordings of MTh and amygdala cells during the expression of learned and innate fear. Next, In Aim #4, we will use a dual viral strategy allowing us to express halorhodopsin or channelrhodopsin, but only in MTh cells that project to the amygdala. We will then optogenetically inhibit or excite amygdala-projecting MTh cells and examine how this affects behavior on amygdala-dependent tasks that probe learned or innate fear. Together, the experiments proposed here will reveal how MTh neurons regulate the excitability of the amygdala during the expression of learned and innate fear. This knowledge will pave the way for pharmacological interventions aiming to regulate the activity of midline thalamic cells by taking advantage of their unusual profile of receptor expression.

Public Health Relevance

Congruent findings from animal and human studies indicate that a highly conserved network of brain structures regulates the expression of fear and anxiety in mammals. The amygdala in particular plays a critical role in various aspects of emotional regulation including the expression of innate fear responses or defensive behaviors, the acquisition of new fear responses as a result of experience and the facilitation of memory by emotions. Importantly, functional imaging studies indicate that the amygdala is often hyper- responsive in humans afflicted with anxiety disorders. As a result, it is commonly believed that many anxiety disorders result, at least in part, from a dysregulation of amygdala processes normally mediating fear/defensive behaviors. Thus, identifying inputs that exert a potent effect on amygdala excitability might open new approaches for the treatment of anxiety disorders. This proposal aims to do just that, by studying the influence of midline thalamic nuclei on the amygdala. Together, the experiments proposed here will reveal how midline thalamic neurons regulate the excitability of the amygdala during the expression of learned and innate fear responses. This knowledge will pave the way for new pharmacological strategies to treat anxiety disorders, by taking advantage of the unusual profile of receptor expression of midline thalamic neurons to regulate their excitability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH107239-03
Application #
9258494
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Vicentic, Aleksandra
Project Start
2015-07-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rutgers University
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
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Amir, Alon; Paré, Jean-Francois; Smith, Yoland et al. (2018) MIDLINE THALAMIC INPUTS TO THE AMYGDALA: ULTRASTRUCTURE AND SYNAPTIC TARGETS. J Comp Neurol :
Kyriazi, Pinelopi; Headley, Drew B; Pare, Denis (2018) Multi-dimensional Coding by Basolateral Amygdala Neurons. Neuron 99:1315-1328.e5
Lee, Seung-Chan; Amir, Alon; Haufler, Darrell et al. (2017) Differential Recruitment of Competing Valence-Related Amygdala Networks during Anxiety. Neuron 96:81-88.e5
Headley, Drew B; Kanta, Vasiliki; Paré, Denis (2017) Intra- and interregional cortical interactions related to sharp-wave ripples and dentate spikes. J Neurophysiol 117:556-565
Paré, Denis; Quirk, Gregory J (2017) WHEN SCIENTIFIC PARADIGMS LEAD TO TUNNEL VISION: LESSONS FROM THE STUDY OF FEAR. NPJ Sci Learn 2:
Headley, Drew B; Paré, Denis (2017) Common oscillatory mechanisms across multiple memory systems. NPJ Sci Learn 2:
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Lee, Seung-Chan; Amir, Alon; Headley, Drew B et al. (2016) Basolateral amygdala nucleus responses to appetitive conditioned stimuli correlate with variations in conditioned behaviour. Nat Commun 7:12275
Jhangiani-Jashanmal, Iman T; Yamamoto, Ryo; Gungor, Nur Zeynep et al. (2016) Electroresponsive properties of rat central medial thalamic neurons. J Neurophysiol 115:1533-41

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