Being Vigilante: New Data on BNST Connectivity in the Nonhuman Primate

Being Vigilant: New Data on BNST Connectivity in the Nonhuman PrimateJulie L. Fudge, MDDepartments of Neuroscience and Psychiatry

No disclosures or conflicts of interest

Anticipation of future events can be pleasant or unpleasant, depending on expectationsPast experience shapes expectations of the futureAnticipatory anxiety can be adaptive, a mechanism to protect the organism should the past repeat itself

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Hermann MJ Human Brain Mapping 2016Brain activity during anticipation of aversive stimulus

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(A) Activation of the right basal forebrain during sustained anticipation of aversion, as overlaid on an anatomical atlas (Mai et al. 1998).

Daniel W. Grupe et al. Cereb. Cortex 2013;23:1874-1883Sustained anticipation of aversion

(A) Activation of the right basal forebrain during sustained anticipation of aversion, as overlaid on an anatomical atlas (Mai et al. 1998). At P < 0.05 (corrected using Monte Carlo simulation), this activation included the dorsal and central BNST (shown in blue), as well as the external globus pallidus (EGP), ventral caudate (CdV), putamen (Pu), vertical limb of the diagonal band (VDB), great terminal island (GTI), and dorsal/posterior portions of the nucleus accumbens (AcL = lateral accumbens core; AcM = medial accumbens shell). ac, anterior commissure; ic, internal capsule, lml, external medullary lamina of the globus pallidus. (B) Sustained anticipation of aversion was accompanied by increased midbrain activity (red) overlapping with the anatomical location of the PAG (blue) and pretectal area (PTc) when overlaid on an anatomical atlas (Mai et al. 1998). PPI analysis revealed an overlapping midbrain cluster (purple) showing increased functional coupling with the anterior mid-cingulate cortex during sustained anticipation. All activations shown at P < 0.05 (corrected using Monte Carlo simulation). Aq, cerebral aqueduct; ctg, central tegmental tract; xscp, decussation of the cerebellar peduncle. Adapted from Mai et al. 1998.

Torrisi et al, Human Brain Mapping, 2015Resting state, 7TUsing the BNST as a seed: what is the resting state intrinsic activity in normal human subjects

Neural activations correlated with threat responses in monkeysFox AS et al , PNAS, 2015

Animals with the most anxious temperament show higher blood flow in a distributed network following exposure to a human intruder6

WHAT ARE THE COMPONENTS OF THE THREAT CIRCUIT AT A CELLULAR LEVEL?

Can circuit organization give us any kind of clue?7

BNST is embedded in the central extended amygdala

BSTL

SLEAcA.

CeNSLEAcB.Fudge, 2001

BSTL is a structure that forms part of the central extended amygdala

Each region is formed of subdivisions that reflect one anotherthe BSTL and CeN are mirror images of one anotherHuge variety of neuropeptides mark the subdivisions and do so similarlyhere neurotensin is seen filling the CeM sleac and BSTLPbut not the lateral central core regions of eachThere are numerous short, associational connections between CeN SLEAc, and BSTLmaking it a coherent macrostructure

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BSTLCeN

SLEAcSLEAcA.B.Fudge, 2001Lesion/inactivation studies show functional dissociations between BNST and CeNBNST related to uncertainty, predator odor, unconditioned stimuli such as light (rodents) (Fendt, 2003; Qi , Walker, Lee). CeN is more classically related to conditioned fear responses (Walker and Davis 1997)

BSTL is a structure that forms part of the central extended amygdala

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Heimer, Alheid, deOlmos 1988, 1999Johnston, 1923

Given the proposed specific role of the BNST in anticipatory, long lasting threat responses, how does the organization of the extended amygdala make sense?

The BLA as a whole does project to the BNSTBut when we parsed inclusion of the injection site, as best we could into those including mainly BSTLcn and the surrounding juxtacapsular region, we found a shift in the projection.12

amygdaladeCampo and Fudge, JCN, 2013

DOING THE CROSS-CHECK: INJECTING ANTEROGRADE TRACERS INTO RETROGRADELY LABELED SITES

MULTIPLE ANTEROGRADE INJECTIONS IN AMYGDALA

IN CONTRAST, MANY ANTEROGRADE INJECTIONS INTO THE AMYGDALA PROJECT THROUGHOUT THE WHOLE EXTENDED AMYGDALA, SO MANY THAT WE COULD BEGIN TO FIGURE OUT WHICH HOW SPECIFIC SUBDIVISIONS OF THE BNST AND CEN ARE TARGETED23

ANTEROGRADE INJECTIONS IN INSULA

INJECTIONS INTO THE INSULA SHOW THE SAMETHEY FORM A CONTINUOUS AFFERENT STREAM TO THE EXTENDED AMYGDALA COVERING BOTH THE BSTL AND CEN ALIKE24

ANTEROGRADE INJECTIONS IN AREA 25 (SUBG ACC)

THE SAME WITH THE VENTRAL ACC (AREA 25) THERE IS A INPUT TO BSTL AND CEN BUT FLOWING IN TO CONTINOUS STREAM.25

AMYGDALAANTERIOR CINGULATEMIDLINE THALAMUSINSULACeNBSTL

HIPPOCAMPUS

Central nucleus projections to the BSTL--retrogradeOler et al. Brain Structure and Function, 2016

Central nucleus projections to the BSTL--anterogradeOler et al. Brain Structure and Function, 2016

BSTL projections to the CeN--retrogradeOler et al. Brain Structure and Function, 2016

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BSTL projections to the CeN--anterogradeOler et al. Brain Structure and Function, 2016

IMMEDIATE FEAR RESPONSESLONG-LASTINGANXIETY-LIKE RESPONSE TOUNCERTAINTYThe BNST/CeN cant be separated. Anatomy suggests that more fear experiences make you more wary about uncertaintyOler et al. Brain Structure and Function, 2016

THE ANATOMY SUGGESTS THAT THERE IS A DIRECT CONDUIT FOR THE SHORT TERM TO INFLUENCE CHRONIC BEHAVIORS33

HIPPOCAMPUS

CeNBSTLAnticipation of aversive or uncertain eventsCoded based on pastmemories?

Sensitized by episodes of fear learning?

Supported by NIMH R0163291, F30MH 096502

Emily Kelly, PhDDana Helmreich, PhDDanielle deCampo, PhDMichele Saul, PhDNancy BuiJulia IourinetsBrian HoBen BergGiovanna BraganzaShahyan RehmanNanette AlcockFUDGE LaboratoryNed Kalins group:Jonathan OlerAndrew FoxRothem Kovner

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